Browsing by Author "Lehloenya, Rannakoe J"

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    Open Access
    Evaluation of the costs of managing cutaneous adverse drug reactions to first-line TB therapy in South African TB patients
    (2018) Knight, Lauren Kerry; Pooran, Anil; Sinanovic, Edina; Lehloenya, Rannakoe J
    Background: Optimal tuberculosis (TB) treatment remains the backbone of effective TB control programmes. However, TB drugs are often associated with adverse drug reactions (ADR) that affect treatment adherence and cure. Cutaneous adverse drug reactions (CADR) are more commonly associated with Human Immunodeficiency Virus (HIV)/TB co-infection, occurring in up to 7% of patients. If severe, CADR require treatment interruption and hospitalisation. There are no standardised guidelines for managing CADR to TB therapy. Current practice in South Africa involves drug rechallenge, a process, which aims to identify the offending drug and modify the treatment regimen. This practice can carry significant risks that need to be weighed against the benefits. Despite significant resources required to manage CADR, there is no available data regarding their economic impact. Alternate strategies to manage TB therapyassociated CADRs and their cost have never been evaluated. The purpose of this study is to evaluate the economic impact of TB therapy-associated CADRs in South Africa and compare the cost of drug rechallenge with alternative strategies. Methods: Data was obtained from 97 patients, admitted to the Groote Schuur Hospital dermatology ward with TB therapy-associated CADR. Clinical data pertaining to hospitalisation, diagnostic/monitoring tests and drug prescriptions was extracted from patient medical records. Healthcare and patient-related costs were obtained from financial department records, interviews and hospital admission records. Alternative drug regimens for CADR management were derived from literature and expert clinical advice. Costs were estimated using an ingredient's approach in 2016 US dollars. A cost-comparative analysis was performed comparing the cost of the current practice with alternative options. Univariate sensitivity analysis was used to investigate the uncertainties around cost components. Results: The cost of managing a TB therapy-associated CADR was $6,525 per patient. Within this population the average cost of managing a CADR in a patient with DS-TB was $5,831 (95% CI: 8438; 10727). The main contributor of CADR costs was hospitalisation amounting to $3,638/patient (62% of total cost). Alternative CADR management strategies using outpatient-initiated second-line regimens containing rifabutin, bedaquiline and delamanid cost 44-55% less than drug rechallenge depending on the drug regimen used ($2,651/patient to $3,276/patient). Sensitivity analyses indicated that drug rechallenge was most sensitive to hospitalisation costs, whereas second-line treatment strategies were sensitive to TB drug costs. The average total loss experienced by patients as a result of the CADR was $530 (25% of their annual income), as compared to an estimated loss in the alternate regimens of $154 (10% of their annual income). Societal costs with alternate regimens were also lower at 46-66% that of current cost of $6,134. Conclusion: CADR to TB treatment represent a significant economic burden to the healthcare system and affected patient. The alternate strategy of outpatient-initiated second-line therapy provides an economically feasible option by implementing an ambulatory practice of care despite using more expensive drugs. Shorter hospitalisation reduces patient and healthcare costs. This data should inform policy makers on optimal resource use within the healthcare system. Once the effectiveness and risk of drugresistance of these strategies has been determined, further research should estimate their cost-effectiveness.
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    Open Access
    Factors associated with increased mortality in a predominantly HIV-infected population with Stevens Johnson syndrome and toxic epidermal necrolysis
    (Public Library of Science, 2014) Knight, Lauren; Muloiwa, Rudzani; Dlamini, Sipho; Lehloenya, Rannakoe J
    Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions with a higher incidence in HIV-infected persons. SJS/TEN are associated with skin and mucosal failure, predisposing to systemic bacterial infection (BSI), a major cause of death. There are limited data on risk factors associated with BSI and and mortality in HIV-infected people with SJS/TEN. METHODS: We conducted a retrospective study of patients admitted to a university hospital with SJS/TEN over a 3 year period. We evaluated their underlying illnesses, eliciting drugs, predictive value of bacterial skin cultures and other factors associated with mortality and BSI in a predominantly HIV-infected population by comparing characteristics of the patients who demised and those who survived. RESULTS: We admitted 86 cases during the study period and 67/86(78%) were HIV-infected. Tuberculosis was the commonest co-morbidity, diagnosed in 12/86(14%) cases. Skin cultures correlated with BSI by the same organism in 7/64(11%) cases and 6/7 were Gram-negative. Two of the 8 cases of Gram-negative BSI had an associated Gram-negative skin culture, although not always the same organism. All 8 fatalities had >30% epidermal detachment, 7 were HIV-infected, 6 died of BSI and 6 had tuberculosis. CONCLUSIONS: Having >30% epidermal detachment in SJS/TEN carries an increased risk of BSI and mortality. Tuberculosis and BSI are associated with higher risk of death in SJS/TEN. Our data suggests there may be an association between Gram-negative BSI and Gram-negative skin infection.
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    Genomics study of anti-tuberculosis drug-induced hypersensitivity reactions
    (2015) Shebe, Khadija Ahmed; Lehloenya, Rannakoe J; Todd, Gail
    Introduction: All first-line anti-tuberculosis drugs can be associated with all phenotypes of cutaneous adverse drug reactions (CADR). Second-line drugs are associated with much poorer outcomes. Thus, identifying the offending drug in poly-pharmacy is difficult. Re -challenge with the drug is the gold standard in identifying the offender, however poses unacceptably high risk of CADR recurrence. Population and drug-specific genomics help identify those susceptible to adverse reactions to a drug facilitating avoidance of the drug. Objective: To investigate the genomic susceptibility in patients with confirmed rifampicin and or isoniazid-associated hypersensitivity reactions using both genome- wide association studies and candidate gene approaches. Methods: A case control study using 14 patients with previous tuberculosis-associated CADR who were re-challenged with first-line anti-tuberculosis drugs and subsequently developed re-challenge reactions to either isoniazid or rifampicin as cases. These were compared with 30 controls who had tolerated rifampicin and isoniazid during the re- challenge process (12 patients, Group 1a) and consecutive patients who had been on TB treatment for at least 12 weeks without developing any adverse drug reaction (1 8 patients, Group 1b) and 200 black South Africans from the general population. HLA genotypes of the samples were determined by SeCore® HLA Sequence based typing (Invitrogen, Life technologies, USA), and potential ambiguities were resolved by sequencing-based typing. Results: We found HLA-B*58:02 (OR=3.6; 95% CI: 1.4-8.99) and HLA-DRB1*09:01 (OR=15.3; 95% CI: 2.1-113.1) to be significantly more prevalent in patients who developed rifampicin and isoniazid-associated CADR as compared to black South African general population. However, we found no significant associations between HLA genotype and rifampicin/isoniazid-associated CADR when we compared the cases to our study controls that had tolerated rifampicin and isoniazid. HLA-B *58.02 was not found to be statistically associated with HIV positive status (p=0.42) and DRESS phenotype ( p= 0.6279). The majority of our cases were black Africans. Approximately 80% of our cases and controls were HIV-infected. DRESS/DIHS was the prevalent phenotype of CADR, accounting for approximately 80% of cases and controls. Discussion: To our knowledge, this is the first study to show an association between HLA-B*58:02 and HLA-DRB1*09:01 alleles and severe cutaneous adverse drugs reactions secondary to rifampicin and isoniazid in an African population. We identify 2 candidate HLA alleles that need confirmation of their association in African patients who develop rifampicin or isoniazid-associated CADR in larger studies. The value of identifying candidate alleles could lead to CADR preventative screening prior to initiating anti-tuberculosis therapy in black South Africans. The HLA-B*58:02 noted in our cases and controls tolerant of the drugs might not be associated with CADR but could be a reflection of the HIV status and control in HIV-TB co-infected persons. Conclusion: HLA-B*58:02 and HLA-DRB1*09:01 may be associated with rifampicin and isoniazid-associated CADR. Alternately HLA-B*58:02 may be associated with HIV status rather than CADR. A sufficiently powered study is needed to confirm this association.
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    In vivo molecular dissection of the effects of HIV-1 in active tuberculosis
    (Public Library of Science, 2016) Bell, Lucy C K; Pollara, Gabriele; Pascoe, Mellissa; Tomlinson, Gillian S; Lehloenya, Rannakoe J; Roe, Jennifer; Meldau, Richard; Miller, Robert F; Ramsay, Alan; Chain, Benjamin M; Dheda, Keertan; Noursadeghi, Mahdad
    Author Summary HIV-1 infected people have substantially increased risk of tuberculosis (TB) leading to a large burden of disease worldwide. We aimed to investigate how HIV-1 causes this effect by altering human immune responses. We measured the products of all immune genes at injection sites of sterilized TB under the skin, in order to look for differences between TB patients with and without HIV-1. We found that the predominant effect of early HIV-1 infection was to diminish a component of immune responses that contributes to prevention of harmful inflammation. In more advanced HIV-1, we found almost complete absence of any immune response to TB except for immune activity which is normally part of our defence against viruses, but may also weaken immune protection against TB. In some patients, TB becomes apparent after starting treatment for HIV-1. In these patients we found that most immune responses had recovered to normal levels, but that one type of response sometimes associated with asthma and allergies was exaggerated. Our findings provide new insights into how HIV-1 can affect immune responses and changes to the immune system that are associated with risk of TB, which will inform the development of new strategies to improve protective immunity.
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    Stevens Johnson Syndrome and toxic epidermal necrolysis: maternal and foetal outcomes in twenty-two consecutive pregnant HIV infected women
    (Public Library of Science, 2015) Knight, Lauren; Todd, Gail; Muloiwa, Rudzani; Matjila, Mushi; Lehloenya, Rannakoe J
    Introduction Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of a rare and life-threatening cutaneous drug reaction. SJS/TEN in pregnancy poses largely unknown risk factors and outcomes for both the mother and foetus compared to the general population. METHODS: We conducted a study of consecutive pregnant women admitted to single tertiary referral centre in South Africa with SJS/TEN over a 3 year period. They were all managed by the same medical team using the same protocols. We evaluated their underlying illnesses, offending drugs and the course of pregnancy and outcomes to determine factors influencing maternal and foetal outcomes. RESULTS: We identified twenty-two women who developed SJS/TEN while pregnant, all of them HIV-infected. Their median age was 29 years. The majority 16/22 (73%) had SJS, the milder variant of the disease affecting < 10% body surface area. Nevirapine was the offending drug in 21/22 (95%) cases. All 22 of the mothers survived with 3/22 (14%) developing postpartum sepsis. Pregnancy outcomes were known in 18/22 women and 9/18 (50%) babies were delivered by caesarean section. There were 2 foetal deaths at 21 and 31 weeks respectively and both were associated with post-partum sepsis. Postnatal complications occurred in 5 cases, 3 involving the respiratory system and the other two being low birth weight deliveries. Eight placentae and one foetus were sent for histology and none showed macroscopic or microscopic features of SJS/TEN. On follow-up, only 12/20 children were tested for HIV at 6 weeks post-delivery and none of them were HIV-infected. All had received prophylactic ARVs including nevirapine. CONCLUSIONS: TEN, the severe form of the disease, was associated with poorer foetal outcomes. SJS/TEN-associated mortality is not increased in HIV-infected pregnant women. Maternal SJS/TEN does not seem to commonly manifest in the foetus.