Browsing by Author "Pepper, Dominique J"
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- ItemOpen AccessAltered ratio of IFN-γ/IL-10 in patients with drug resistant Mycobacterium tuberculosis and HIV-tuberculosis immune reconstitution inflammatory syndrome(Public Library of Science, 2012) Skolimowska, Keira H; Rangaka, Molebogeng X; Meintjes, Graeme; Pepper, Dominique J; Seldon, Ronnett; Matthews, Kerryn; Wilkinson, Robert J; Wilkinson, Katalin AWe have described a clinical relationship between HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and anti-tubercular drug resistance. Here we studied the immune response of TB-IRIS patients from whom a drug-resistant (n = 11) or drug-susceptible (n = 25) Mycobacterium tuberculosis (MTB) strain was isolated after presenting with TB-IRIS. ELISpot analysis and multiplex cytokine analysis of the supernatant collected from peripheral blood mononuclear cells stimulated overnight with the heat-killed H37Rv MTB laboratory strain was used. Although there was no statistical difference in IFN-gamma ELISpot responses between the two groups, the results point towards higher bacterial load in the drug-resistant patients, possibly due to failed therapy. The ratio between secreted IFN-gamma/IL-10 and IL-2/IL-10 was significantly lower in TB-IRIS patients in whom the cause of TB was a drug-resistant strain compared to those with a fully sensitive strain (p = 0.02). Since host immune responses are dependent on the bacterial load, we hypothesise that the impaired cytokine balance is likely to be caused by the poorly controlled bacterial growth in these patients.
- ItemOpen AccessAssessment at antiretroviral clinics during TB treatment reduces loss to follow-up among HIV-infected patients(Public Library of Science, 2012) Pepper, Dominique J; Marais, Suzaan; Bhaijee, Feriyl; Wilkinson, Robert J; De Azevedo, Virginia; Meintjes, GraemeSetting: A South African township clinic where loss to follow-up during TB treatment may prevent HIV-infected TB patients from receiving life-saving ART. Objective: To determine factors associated with loss to follow-up during TB treatment. Design: Regression analyses of a cohort of ART-eligible TB patients who commenced TB treatment and were followed for 24 weeks. RESULTS: Of 111 ART-eligible TB patients, 15 (14%) died in the ensuing 24 weeks. Of the remaining 96 TB patients, 11 (11%) were lost to follow-up. All TB patients lost to follow-up did not initiate ART. Of 85 TB patients in follow-up, 62 (73%) initiated ART 56 days after TB diagnosis (median, IQR 33-77 days) and 31 days after initial assessment at an ART clinic (median, IQR: 18-55 days). The median duration from TB diagnosis to initial assessment at an ART clinic was 19 days (IQR: 7-48 days). At 24 weeks, 6 of 85 (7%) TB patients who presented to an ART clinic for assessment were lost to follow-up, compared to 5 of 11 (45%) TB patients who did not present to an ART clinic for assessment. Logistic regression analysis (adjusted odds ratio = 0.1, 95% confidence interval [95% CI]: 0.03-0.66) and our Cox proportional hazards model (hazard ratio = 0.2, 95% CI: 0.04-0.68) confirmed that assessment at an ART clinic during TB treatment reduced loss to follow-up. CONCLUSION: Assessment at antiretroviral clinics for HIV care by trained health-care providers reduces loss to follow-up among HIV-infected patients with TB.
- ItemOpen AccessBarriers to initiation of antiretrovirals during antituberculosis therapy in Africa(Public Library of Science, 2011) Pepper, Dominique J; Marais, Suzaan; Wilkinson, Robert J; Bhaijee, Feriyl; De Azevedo, Virginia; Meintjes, GraemeBACKGROUND: In the developing world, the principal cause of death among HIV-infected patients is tuberculosis (TB). The initiation of antiretroviral therapy (ART) during TB therapy significantly improves survival, however it is not known which barriers prevent eligible TB patients from initiating life-saving ART. Method Setting. A South African township clinic with integrated tuberculosis and HIV services. Design. Logistic regression analyses of a prospective cohort of HIV-1 infected adults (≥18 years) who commenced TB therapy, were eligible for ART, and were followed for 6 months. FINDINGS: Of 100 HIV-1 infected adults eligible for ART during TB therapy, 90 TB patients presented to an ART clinic for assessment, 66 TB patients initiated ART, and 15 TB patients died. 34% of eligible TB patients (95%CI: 25-43%) did not initiate ART. Male gender and younger age (<36 years) were associated with failure to initiate ART (adjusted odds ratios of 3.7 [95%CI: 1.25-10.95] and 3.3 [95%CI: 1.12-9.69], respectively). Death during TB therapy was associated with a CD4+ count <100 cells/µL. CONCLUSION: In a clinic with integrated services for tuberculosis and HIV, one-third of eligible TB patients - particularly young men - did not initiate ART. Strategies are needed to promote ART initiation during TB therapy, especially among young men.
- ItemRestrictedCentral nervous system disorders afrer starting antiretroviral therapy in South Africa(Lippincott, Williams & Wilkins, 2010) Asselman, Valerie; Thienemann, Fredrich; Pepper, Dominique J; Boulle, Andrew; Wilkinson, Robert J; Graeme Meintjes; Marais, SuzaanObjective: To describe the spectrum of central nervous system (CNS) disease during the first year of antiretroviral therapy (ART), and to determine the contribution of neurological immune reconstitution inflammatory syndrome (IRIS). Design: A prospective observational cohort study conducted over a 12-month period at a public sector referral hospital in South Africa. Methods: HIV seropositive patients who developed new or recurrent neurological or psychiatric symptom(s) or sign(s) within the first year of starting ART were enrolled. We used the number of patients starting ART in the referral area in the preceding year as the denominator to calculate the incidence of referral for neurological deterioration. Patients with delirium and peripheral neuropathy were excluded. Outcome at six months was recorded. Results: Seventy-five patients were enrolled. The median nadir CD4+ count was 64 cells/μL. 59% of patients were receiving antituberculosis treatment. The incidence of referral for CNS deterioration in the first year of ART was 23.3 cases (95% CI, 18.3–29.2) per 1000 patient years at risk. CNS tuberculosis (n=27, 36%), cryptococcal meningitis (n=18, 24%), intracerebral space occupying lesions (other than tuberculoma) (n=10, 13%) and psychosis (n=9, 12%) were the most frequent diagnoses. Paradoxical neurological IRIS was diagnosed in 21 patients (28%), related to tuberculosis in 16 and cryptococcosis in 5. At 6 months, 23% of patients had died and 20% were lost to follow-up. Conclusion: Opportunistic infections, notably tuberculosis and cryptococcosis, were the most frequent causes for neurological deterioration after starting ART. Neurological IRIS occurred in over a quarter of patients.
- ItemOpen AccessClinical deterioration during antitubercular treatment at a district hospital in South Africa: the importance of drug resistance and AIDS defining illnesses(Public Library of Science, 2009) Pepper, Dominique J; Rebe, Kevin; Morroni, Chelsea; Wilkinson, Robert J; Meintjes, GraemeBACKGROUND: Clinical deterioration on drug therapy for tuberculosis is a common cause of hospital admission in Africa. Potential causes for clinical deterioration in settings of high HIV-1 prevalence include drug resistant Mycobacterium tuberculosis (M.tb) , co-morbid illnesses, poor adherence to therapy, tuberculosis associated-immune reconstitution inflammatory syndrome (TB-IRIS) and subtherapeutic antitubercular drug levels. It is important to derive a rapid diagnostic work-up to determine the cause of clinical deterioration as well as specific management to prevent further clinical deterioration and death. We undertook this study among tuberculosis (TB) patients referred to an adult district level hospital situated in a high HIV-1 prevalence setting to determine the frequency, reasons and outcome for such clinical deterioration. Method A prospective observational study conducted during the first quarter of 2007. We defined clinical deterioration as clinical worsening or failure to stabilise after 14 or more days of antitubercular treatment, resulting in hospital referral. We collected data on tuberculosis diagnosis and treatment, HIV-1 status and antiretroviral treatment, and investigated reasons for clinical deterioration as well as outcome. RESULTS: During this period, 352 TB patients met inclusion criteria; 296 were admitted to hospital accounting for 17% of total medical admissions (n = 1755). Eighty three percent of TB patients (291/352) were known to be HIV-1 co-infected with a median CD4 count of 89cells/mm 3 (IQR 38-157). Mortality among TB patients admitted to hospital was 16% (n = 48). The median duration of hospital admission was 9.5 days (IQR 4-18), longer than routine in this setting (4 days). Among patients in whom HIV-1 status was known (n = 324), 72% of TB patients (n = 232) had an additional illness to tuberculosis; new AIDS defining illnesses (n = 80) were the most frequent additional illnesses (n = 208) in HIV-1 co-infected patients (n = 291). Rifampin-resistant M.tb (n = 41), TB-IRIS (n = 51) and drug resistant bacterial infections (n = 12) were found in 12%, 14% and 3.4% of the 352 cases, respectively. Interpretation In our setting, new AIDS defining illnesses, drug resistant M.tb and other drug resistant bacteria are important reasons for clinical deterioration in HIV-1 co-infected patients receiving antitubercular treatment. HIV-1 co-infected patients may be at increased risk of acquiring nosocomial drug resistant pathogens because profound immune suppression results in co-morbid illnesses that require prolonged inpatient admissions. Routine infection control is essential and needs to be strengthened in our setting.
- ItemOpen AccessPresentation and outcome of tuberculous meningitis in a high HIV prevalence setting(Public Library of Science, 2011) Marais, Suzaan; Pepper, Dominique J; Schutz, Charlotte; Wilkinson, Robert J; Meintjes, GraemeBACKGROUND: Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM. METHODS: A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009-August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions. RESULTS: TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08-0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4 + count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03-1.96) per 50 cells/µL drop in CD4 + count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45-15.87). Interpretation Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.
- ItemOpen AccessProlonged tuberculosis-associated immune reconstitution inflammatory syndrome: characteristics and risk factors(BioMed Central, 2016-09-27) Bana, Tasnim M; Lesosky, Maia; Pepper, Dominique J; van der Plas, Helen; Schutz, Charlotte; Goliath, Rene; Morroni, Chelsea; Mendelson, Marc; Maartens, Gary; Wilkinson, Robert J; Meintjes, GraemeBackground: In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS. Methods: We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher’s exact test, multivariate logistic regression and Cox proportional hazards models. Results: Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0–113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13–4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of borderline significance (aOR 3.26, 95 % CI 0.97–12.99). The association of not being hospitalised with longer duration of IRIS might be related to 1 of the 3 cohorts in which all patients were hospitalised at ART initiation with close inpatient follow-up. This could have resulted in diagnosis of milder cases and earlier IRIS treatment potentially resulting in shorter TB-IRIS duration in these hospitalised patients. Conclusions: Around 40 % of patients with TB-IRIS have symptoms for more than 90 days. Involvement of lymph nodes at time of TB-IRIS is an independent risk factor for prolonged TB-IRIS. Future studies should address whether more prompt anti-inflammatory treatment of lymph node TB-IRIS reduces the risk of prolonged TB-IRIS. Trial registration: The randomized controlled trial was registered with Current Controlled Trials ISRCTN21322548 on 17 August 2005.
- ItemRestrictedRandomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome(Lippincott, Williams & Wilkins, 2010) Meintjes, Graeme; Wilkinson, Robert J; Morroni, Chelsea; Pepper, Dominique J; Rebe, Kevin; Rangaka, Molebogeng X; Oni, Tolu; Maartens, GaryObjective: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of antiretroviral therapy in resource-limited countries. We aimed to assess whether a 4 week course of prednisone would reduce morbidity in patients with paradoxical TB-IRIS without excess adverse events. Design: A randomised double blind placebo-controlled trial of prednisone (1.5mg/kg/day for 2 weeks then 0.75mg/kg/day for 2 weeks). Patients with immediately life-threatening TB-IRIS manifestations were excluded. Methods: The primary combined endpoint was days of hospitalization and outpatient therapeutic procedures, which were counted as one hospital day. Results: 110 participants were enrolled (55 to each arm). The primary combined endpoint was more frequent in the placebo than the prednisone arm (median hospital days 3 (IQR 0-9) and 0 (IQR 0-3) respectively; p=0.04). There were significantly greater improvements in symptoms, Karnofsky score, and quality of life (MOS-HIV) in the prednisone versus the placebo arm at 2 and 4 weeks, but not at later timepoints. Chest radiographs improved significantly more in the prednisone arm at weeks 2 (p=0.002) and 4 (p=0.02). Infections on study medication occurred in more participants in prednisone than placebo arm (27 vs 17 respectively; p=0.05), but there was no difference in severe infections (2 vs 4 respectively; p=0.40). Isolates from 10 participants were found to be resistant to rifampicin after enrollment. Conclusions: Prednisone reduced the need for hospitalisation and therapeutic procedures, and hastened improvements in symptoms, performance and quality of life. It is important to investigate for drug-resistant tuberculosis and other causes for deterioration before administering glucocorticoids.