Browsing by Subject "Toxicity"
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- ItemOpen AccessComplications of antiretroviral therapy initiation in hospitalised patients with HIV-associated tuberculosis(Public Library of Science, 2013) van der Plas, Helen; Meintjes, Graeme; Schutz, Charlotte; Goliath, Rene; Myer, Landon; Baatjie, Dorothea; Wilkinson, Robert J; Maartens, Gary; Mendelson, MarcBACKGROUND: HIV-associated tuberculosis is a common coinfection in Sub-Saharan Africa, which causes high morbidity and mortality. A sub-set of HIV-associated tuberculosis patients require prolonged hospital admission, during which antiretroviral therapy initiation may be required. The aim of this study was to document the causes of clinical deterioration of hospitalised patients with HIV-associated tuberculosis starting antiretroviral therapy in order to inform healthcare practice in low- to middle-income countries. METHODS: Prospective, observational cohort study of adult inpatients with HIV-associated tuberculosis starting antiretroviral therapy in a dedicated tuberculosis hospital in Cape Town, South Africa. Causes of clinical deterioration and outcome were recorded in the first 12 weeks of antiretroviral therapy. Patients with rifampicin-resistant tuberculosis were excluded. RESULTS: Between May 2009 and November 2010, 112 patients (60% female), with a median age of 32 years were enrolled. At baseline the median CD4 count was 55 cells/mm 3 (IQR 31-106) and HIV viral load 5.6 log copies/mL. All patients had significant comorbidity: 82% were bed-bound, 65% had disseminated tuberculosis and 27% had central nervous system tuberculosis. Seventy six patients (68%) developed 144 clinical events after starting antiretroviral therapy. TB-IRIS, hospital-acquired infections and significant drug toxicities occurred in 42%, 20.5% and 15% of patients respectively. A new opportunistic disease occurred in 15% of patients and a thromboembolic event in 8%. Mortality during the 12 week period was 10.6%. CONCLUSIONS: High rates of TB-IRIS, hospital-acquired infections and drug toxicities complicate the course of patients with HIV-associated tuberculosis starting antiretroviral therapy in hospital. Despite the high morbidity, mortality was relatively low. Careful clinical management and adequate resources are needed in hospitalised HIV-TB patients in the 1 st three months following ART initiation.
- ItemOpen AccessEffects of long-term organophosphate exposures on neurological symptoms, vibration sense and tremor amongst South African farm workers(1998) London, Leslie; Nell, V; Thompson, M L; Myers, J EOBJECTIVES: This study assessed the relationship between long-term exposure to organophosphate insecticides and neurological symptoms, vibration sense, and motor tremor after control for the effect of past poisoning and acute exposure. METHODS: This cross-sectional study included 164 pesticide applicators and 83 nonspraying reference workers on deciduous fruit farms. The workers were tested on the Vibratron II, on tests of dynamic and static tremor, and for a set of neurological and "dummy" symptoms. Exposure was derived with the use of a job-exposure matrix for pesticides in agriculture. RESULTS: Compared with nonapplicators, current applicators reported significantly more dizziness, sleepiness, and headache and had a higher overall neurological symptom score. This association remained statistically significant after multiple logistic regression analyses controlling for a range of confounders and effect modifiers [odds ratio (OR) 2.25, for current applicators having high neurological score, 95% confidence interval (95% CI) 1.15-4.39]. The average lifetime intensity of organophosphate exposure was nonsignificantly associated with both neurological (OR 1.98, 95% CI 0.49-7.94) and "dummy" symptoms (OR 2.37, 95% CI 0.54-10.35). Previous pesticide poisoning was significantly associated with the neurological scores (OR 4.08, 95% CI 1.48-11.22) but not with the "dummy" symptoms. Vibration sense outcomes were associated with age and height, but not with the organophosphate exposure measures. In the multiple linear regression modeling for tremor intensity in the dominant hand, recent organophosphate exposure in the past 10 days was a significant predictor (partial correlation coefficient = 0.04), but none of the long-term organophosphate exposure measures were significant. CONCLUSIONS: Strong evidence was found for an association between symptom outcomes and past organophosphate poisoning and between symptom outcomes and current spray activity. In contrast to symptoms, there was no association between either past poisoning or current spray activity and vibration sense or tremor outcome. Long-term organophosphate exposure did not appear to predict symptoms, vibration sense, or tremor outcome.
- ItemOpen AccessFactors associated with elevated blood lead levels in inner city Cape Town children(1991) von Schirnding, Y E; Fuggle, R F; Bradshaw, DA cross-sectional analytical study was carried out to determine risk factors for childhood lead exposure. Blood lead levels of inner-city Sub A coloured children living in Woodstock were examined in relation to information obtained by questionnaire on environmental and social factors. The mean blood lead concentration of the population was 18 micrograms/dl. Thirteen per cent of children had blood lead levels greater than or equal to 25 micrograms/dl, the present USA 'action' level. Dusty homes and homes in a poor state of repair, over-crowding, low parental education and income, and other aspects related to family structure and socio-economic status, were associated with raised blood lead levels. It is suggested that social factors assume importance in predisposing children to lead in the environment. In particular, the over-crowded nature of the homes could have a direct bearing on the quality of the care-giving environment, providing opportunity for children's activities to go unsupervised. This could lead young children to be more exposed to accessible sources of lead associated with poor housing conditions. More attention needs to be given to examining the interaction of social and environmental factors in studies of childhood lead exposure.
- ItemOpen AccessA high-throughput screen against pantothenate synthetase (PanC) identifies 3-biphenyl-4-cyanopyrrole-2-carboxylic acids as a new class of inhibitor with activity against Mycobacterium tuberculosis(Public Library of Science, 2013) Kumar, Anuradha; Casey, Allen; Odingo, Joshua; Kesicki, Edward A; Abrahams, Garth; Vieth, Michal; Masquelin, Thierry; Mizrahi, Valerie; Hipskind, Philip A; Sherman, David RThe enzyme pantothenate synthetase, PanC, is an attractive drug target in Mycobacterium tuberculosis . It is essential for the in vitro growth of M. tuberculosis and for survival of the bacteria in the mouse model of infection. PanC is absent from mammals. We developed an enzyme-based assay to identify inhibitors of PanC, optimized it for high-throughput screening, and tested a large and diverse library of compounds for activity. Two compounds belonging to the same chemical class of 3-biphenyl-4- cyanopyrrole-2-carboxylic acids had activity against the purified recombinant protein, and also inhibited growth of live M. tuberculosis in manner consistent with PanC inhibition. Thus we have identified a new class of PanC inhibitors with whole cell activity that can be further developed.
- ItemOpen AccessA novel Markov model projecting costs and outcomes of providing antiretroviral therapy to public patients in private practices versus public clinics in south Africa(Public Library of Science, 2013) Leisegang, Rory; Maartens, Gary; Hislop, Michael; Sargent, John; Darkoh, Ernest; Cleary, SusanIntroduction Providing private antiretroviral therapy (ART) care for public sector patients could increase access to ART in low- and middle-income countries. We compared the costs and outcomes of a private-care and a public-care ART program in South Africa. METHODS: A novel Markov model was developed from the public-care program. Patients were first tunneled for 6 months in their baseline CD4 category before being distributed into a dynamic CD4 and viral load model. Patients were allowed to return to ART care from loss to follow up (LTFU). We then populated this modeling framework with estimates derived from the private-care program to externally validate the model. RESULTS: Baseline characteristics were similar in the two programs. Clinic visit utilization was higher and death rates were lower in the first few years on ART in the public-care program. After 10 years on ART we estimated the following outcomes in the public-care and private-care programs respectively: viral load <1000 copies/ml 89% and 84%, CD4 >500 cells/μl 33% and 37%, LTFU 14% and 14%, and death 27% and 32%. Lifetime undiscounted survival estimates were 14.1 (95%CI 13.2-14.9) and (95%CI 12.7-14.5) years with costs of 18,734 (95%CI 12,588-14,022) and 13,062 (95%CI 12,077-14,047) USD in the private-care and public-care programs respectively. When clinic visit utilization in the public-care program was reduced by two thirds after the initial 6 months on ART, which is similar to their current practice, the costs were comparable between the programs. CONCLUSIONS: Using a novel Markov model, we determined that the private-care program had similar outcomes but lower costs than the public-care program, largely due to lower visit frequencies. These findings have important implications for increasing and sustaining coverage of patients in need of ART care in resource-limited settings.
- ItemOpen AccessRates of switching antiretroviral drugs in a primary care service in South Africa before and after introduction of tenofovir(Public Library of Science, 2013) Njuguna, Christine; Orrell, Catherine; Kaplan, Richard; Bekker, Linda-Gail; Wood, Robin; Lawn, Stephen DIntroduction Antiretroviral changes (single drug substitutions and regimen switches) limit treatment options and introduce challenges such as increased cost, monitoring and adherence difficulties. Patterns of drug substitutions and regimen switches from stavudine (d4T) and zidovudine (AZT) regimens have been well described but data on tenofovir (TDF) are more limited. This study describes the patterns and risk factors for drug changes of these antiretroviral drugs in adults. Method This retrospective cohort study included HIV positive, antiretroviral treatment (ART) naïve adults aged ≥18 years who started ART with two nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor. Follow-up was censored at first drug change and analysis focused on NRTI changes only. RESULTS: Between September 2002 and April 2011, 5095 adults initiated ART in Gugulethu. This comprised 948 subjects on TDF, 3438 on d4T and 709 subjects on AZT. Virological suppression rates at 1 year, regimen switching due to virological failure and overall losses to the programme were similar across the three groups. TDF had the lowest incidence rate of drug substitutions (2.6 per 100 P/Ys) compared to 17.9 for d4T and 8.5 per 100 P/Ys for AZT. Adverse drug reactions (ADRs) accounted for the majority of drug substitutions of d4T. Multivariate analysis showed that increasing age, female sex and d4T exposure were associated with increased hazard of drug substitution due to ADRs. Conversely, TDF exposure was associated with a substantially lower risk of substitution (adjusted hazards ratio 0.38; 95% CI 0.20-0.72). CONCLUSION: Regimen switches and virological suppression were similar for patients exposed to TDF, d4T and AZT, suggesting all regimens were equally effective. However, TDF was better tolerated with a substantially lower rate of drug substitutions due to ADRs.
- ItemOpen AccessRenal safety of a tenofovir-containing first line regimen: experience from an antiretroviral cohort in rural Lesotho(Public Library of Science, 2011) Bygrave, Helen; Kranzer, Katharina; Hilderbrand, Katherine; Jouquet, Guillaume; Goemaere, Eric; Vlahakis, Nathalie; Triviño, Laura; Makakole, Lipontso; Ford, NathanIntroduction Current guidelines contraindicate TDF use when creatinine clearance (CrCl) falls below 50 ml/min. We report prevalence of abnormal renal function at baseline and factors associated with abnormal renal function from a community cohort in Lesotho. METHODS: We calculated changes in CrCl from baseline for patients initiated on TDF at 6 and 12 months and the proportion of patients initiated on TDF who developed renal impairment. Screening algorithms were developed using risk factors determined by multivariate analysis. RESULTS: Among 933 adults for whom baseline creatinine was available, 176 (18.9%) presented with a baseline CrCl <50 ml/min. Renal function improved during follow-up. 19 patients who developed renal toxicity during follow up remained on TDF; renal function improved (CrCl≥50 ml/min) in all but 3 of these patients. Among 15 patients with a baseline CrCl <50 ml/min were started in error, none developed severe renal impairment. CONCLUSION: In this setting TDF-associated renal toxicity is rare and mainly transient. Further studies to assess TDF safety at lower CrCl thresholds are warranted.
- ItemOpen AccessThe safety, effectiveness and concentrations of adjusted lopinavir/ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy(Public Library of Science, 2012) Decloedt, Eric H; Maartens, Gary; Smith, Peter; Merry, Concepta; Bango, Funeka; McIlleron, HelenObjective Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment. METHODS: Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month. RESULTS: 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1-9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable. CONCLUSION: Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate.
- ItemOpen AccessStavudine toxicity in adult longer-term ART patients in Blantyre, Malawi(Public Library of Science, 2012) van Oosterhout, Joep J; Mallewa, Jane; Kaunda, Symon; Chagoma, Newton; Njalale, Yassin; Kampira, Elizabeth; Mukaka, Mavuto; Heyderman, Robert SBACKGROUND: Stavudine is an effective and inexpensive antiretroviral drug, but no longer recommended by WHO for first-line antiretroviral regimens in resource-limited settings due to toxicity concerns. Because of the high cost of alternative drugs, it has not been feasible to replace stavudine in most adults in the Malawi ART programme. We aimed to provide policy makers with a detailed picture of stavudine toxicities in Malawians on longer-term ART, in order to facilitate prioritization of stavudine replacement among other measures to improve the quality of ART programmes. METHODS: Prospective cohort of Malawian adults who had just completed one year of stavudine containing ART in an urban clinic, studying peripheral neuropathy, lipodystrophy, diabetes mellitus, high lactate syndromes, pancreatitis and dyslipidemia during 12 months follow up. Stavudine dosage was 30 mg irrespective of weight. Cox regression was used to determine associations with incident toxicities. RESULTS: 253 patients were enrolled, median age 36 years, 62.5% females. Prevalence rates (95%-confidence interval) of toxicities after one year on stavudine were: peripheral neuropathy 21.3% (16.5-26.9), lipodystrophy 14.7% (2.4-8.1), high lactate syndromes 0.0% (0-1.4), diabetes mellitus 0.8% (0-2.8), pancreatitis 0.0% (0-1.5). Incidence rates per 100 person-years (95%-confidence interval) during the second year on stavudine were: peripheral neuropathy 19.8 (14.3-26.6), lipodystrophy 11.4 (7.5-16.3), high lactate syndromes 2.1 (0.7-4.9), diabetes mellitus 0.4 (0.0-1.4), pancreatitis 0.0 (0.0-0.2). Prevalence of hypercholesterolemia and hypertriglyceridemia increased from 12.1% to 21.1% and from 29.5% to 37.6% respectively between 12 and 24 months. 5.5% stopped stavudine, 1.3% died and 4.0% defaulted during follow up. Higher age was an independent risk factor for incident peripheral neuropathy and lipodystrophy. CONCLUSION: Stavudine associated toxicities continued to accumulate during the second year of ART, especially peripheral neuropathy and lipodystrophy and more so at increasing age. Our findings support investments for replacing stavudine in first-line regimens in sub-Saharan Africa.
- ItemOpen AccessToxicity associated with tuberculosis chemotherapy in the REMoxTB study(BioMed Central, 2018-07-11) Tweed, Conor D; Crook, Angela M; Amukoye, Evans I; Dawson, Rodney; Diacon, Andreas H; Hanekom, Madeline; McHugh, Timothy D; Mendel, Carl M; Meredith, Sarah K; Murphy, Michael E; Murthy, Saraswathi E; Nunn, Andrew J; Phillips, Patrick P J; Singh, Kasha P; Spigelman, Melvin; Wills, Genevieve H; Gillespie, Stephen HAbstract Background The incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin. Methods All grade 3 & 4 adverse events (AEs) and their relationship to treatment for patients who had taken at least one dose of therapy in the REMoxTB clinical trial were recorded. Univariable logistic regression was used to test the relationship of baseline characteristics to the incidence of grade 3 & 4 AEs and significant characteristics (p < 0.10) were incorporated into a multivariable model. The timing of AEs during therapy was analysed in standard therapy and the experimental arms. Logistic regression was used to investigate the relationship between AEs (total and related-only) and microbiological cure on treatment. Results In the standard therapy arm 57 (8.9%) of 639 patients experienced ≥1 related AEs with 80 of the total 113 related events (70.8%) occurring in the intensive phase of treatment. Both four-month experimental arms (“isoniazid arm” with moxifloxacin substituted for ethambutol & “ethambutol arm” with moxifloxacin substituted for isoniazid) had a lower total of related grade 3 & 4 AEs than standard therapy (63 & 65 vs 113 AEs). Female gender (adjOR 1.97, 95% CI 0.91–1.83) and HIV-positive status (adjOR 3.33, 95% CI 1.55–7.14) were significantly associated with experiencing ≥1 related AE (p < 0.05) on standard therapy. The most common adverse events on standard therapy related to hepatobiliary, musculoskeletal and metabolic disorders. Patients who experienced ≥1 related AE were more likely to fail treatment or relapse (adjOR 3.11, 95% CI 1.59–6.10, p < 0.001). Conclusions Most AEs considered related to standard therapy occurred in the intensive phase of treatment with female patients and HIV-positive patients demonstrating a significantly higher risk of AEs during treatment. Almost a tenth of standard therapy patients had a significant side effect, whereas both experimental arms recorded a lower incidence of toxicity. That patients with one or more AE are more likely to fail treatment suggests that treatment outcomes could be improved by identifying such patients through targeted monitoring.
- ItemOpen AccessTreatment Interruption and Variation in Tablet Taking Behaviour Result in Viral Failure: A Case-Control Study from Cape Town, South Africa(Public Library of Science, 2011) Ncaca, Lisa-Noelle; Kranzer, Katharina; Orrell, CatherineBACKGROUND: Understanding of the impact of non-structured treatment interruption (TI) and variation in tablet-taking on failure of first-line antiretroviral therapy (ART) is limited in a resource-poor setting. METHODS: A retrospective matched case-control analysis. Individuals failing ART were matched by time on ART with 4 controls. Viral load (VL) and CD4 count were completed 4-monthly. Adherence percentages, from tablet returns, were calculated 4-monthly (interval) and from ART start (cumulative). Variation between intervals and TI (>27 days off ART) were recorded. Conditional multivariate logistic regression analysis was performed to estimate the effect of cumulative adherence <90%, at least one episode of adherence variation >10% and TI on virological failure. Age, gender, baseline log VL and CD4 were included as possible confounders in the multivariate model. RESULTS: 244 patients (44 cases, 200 controls) were included. Median age was 32 years (IQR28-37), baseline CD4 108 cells/mm3 (IQR56-151), VL 4.82 log (IQR4.48-5.23). 94% (96% controls, 86% failures) had cumulative adherence >90%. The odds of failure increased 3 times (aOR 3.01, 95%CI 0.81-11.21) in individuals with cumulative adherence <90%, 2.2 times (aOR 2.20, 95%CI 1.04-4.64) in individuals with at least one episode of fluctuating adherence of >10% and 4.01 times (aOR 4.01, 95%CI 1.45-11.10) in individuals with TIs. For individuals with TI and cumulative adherence >95%, the odds of failing were 5.65 (CI 1.40-22.85). CONCLUSION: It is well known that poor cumulative adherence increases risk of virological failure, but less well understood that TI and variations in tablet-taking also play a key role, despite otherwise excellent adherence.
- ItemOpen AccessWhat is the optimal first line antiretroviral therapy in resource-limited settings?(Public Library of Science, 2012) Kenyon, Chris; Colebunders, RobertA perspective by Chris Kenyon and Robert Colebunders discusses policy implications for use of first line antiretroviral therapies in resource-limited settings, emerging from a new research study conducted by Campbell and colleagues.