Browsing by Author "Maartens, Gary"
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- ItemOpen AccessA pharmacometric approach to optimal use of second line drugs for multidrug-resistant tuberculosis(2023) Court, Richard Gray; Mcilleron, Helen; Maartens, GaryUntil the recent introduction of short course regimens, treatment regimens for multidrug resistant TB (MDR-TB) were long and toxic. Consequently, only approximately half of MDRTB patients completed their treatment. TB dosing guidelines have historically been unrefined with little consideration for pharmacokinetic/pharmacodynamic relationships. Large knowledge gaps therefore exist in the understanding of pharmacokinetic/pharmacodynamic relationships for both efficacy and toxicity in MDR-TB. My PhD used clinical pharmacology approaches to improve the understanding of drug exposures, toxicity, and exposure-toxicity relationships during the first 12 weeks of MDR-TB therapy. Aims and methods 1. Using non-compartmental analyses, describe the pharmacokinetics of cycloserine and, using regression modelling, explore the association of covariates with cycloserine exposure. 2. Using validated screening tools, describe the incidence of neuropsychiatric toxicity in MDR-TB patients, and explore associations with cycloserine pharmacokinetics. 3. Using a validated pain-rating scale in a crossover study design, investigate whether the addition of a local anaesthetic reduces kanamycin-related injection pain, and explore effects on kanamycin pharmacokinetics. 4. Using geometric mean ratios, compare the exposures of crushed versus whole formulations of pyrazinamide, moxifloxacin, ethionamide, ethambutol, cycloserine, and isoniazid. Results and conclusions We found no measurable terizidone in plasma supporting the hypothesis that terizidone is hydrolysed pre-systemically to cycloserine. The cycloserine time-concentration profile supports once daily dosing of terizidone. We describe a high incidence of peripheral neuropathy in MDR-TB patients with both cycloserine clearance and high-dose pyridoxine significantly associated with neuropathy on multivariate analysis. The addition of a local anaesthetic reduced the pain experienced by MDR-TB patients in the first 15 minutes post intramuscular administration of kanamycin, which could improve adherence to MDR-TB treatment. We also found the bioavailability of crushed isoniazid to be approximately 42% less than the whole tablet formulation, and therefore recommend that the crushing of isoniazid be avoided. Although some recent treatment advances have improved MDR-TB outcomes, enhancing the understanding of drugs used to treat MDR-TB, which continues to have an unacceptably high mortality and treatment-related morbidity, is a public health priority. This thesis comprises four peer-reviewed publications, all of which made a pragmatic contribution to the fight against MDR-TB.
- ItemOpen AccessAdverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases(2019-06-20) Jones, Jackie; Mudaly, Vanessa; Voget, Jacqueline; Naledi, Tracey; Maartens, Gary; Cohen, KarenBackground Bedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme. Methods We reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. “Confirmed ADRs” included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient’s death as follows: major contributor, contributor or non-contributor. Results Thirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as “possible” and seven as “probable”. Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths. Conclusions Confirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity.
- ItemOpen AccessAn evidence-based algorithm for the rapid diagnosis of tuberculosis in HIV positive patients presenting to emergency centres(2021) van Hoving, Daniël J; Meintjes, Graeme; Maartens, Gary; Kenge, AndreBackground Tuberculosis remains a prevalent and deadly global disease. Diagnostic delays are partly due to reduced diagnostic performance of tuberculosis tests in HIV-positive people. The use of reliable pointof-care and near-patient diagnostic tests (e.g. urine lipoarabinomannan and point-of-care ultrasound) are increasingly being used and would benefit patients presenting to emergency centres by rapidly diagnosing HIV-associated tuberculosis. Methods Two studies were done: i) A systematic (Cochrane) review was done to determine the diagnostic accuracy of abdominal ultrasound for detecting abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals, and ii) A cross-sectional diagnostic study to derive a multi-parameter clinical decision tree, incorporating clinical information, point-of-care ultrasound features, chest x-ray and urine lateral flow lipoarabinomannan. The cross-sectional study was performed at the emergency centre of Khayelitsha Hospital, a South African district-level hospital in a high HIV-prevalence community, and resulted in three different publications. Consecutive HIV-positive adults presenting with ≥1 WHO tuberculosis symptoms were enrolled over a 16-month period (June 2016 to October 2017). Demographic and clinical information was recorded on a standardized data collection form. Point-of-care ultrasound was performed according to a standardized protocol. Urine lipoarabinomannan assays were done at point-of-care by emergency physicians and repeated in the laboratory. Chest x-rays were reviewed by a single radiologist using a standardized assessment form. The reference standard was a positive tuberculosis culture or Xpert MTB/RIF test on sputum, or appropriate extra-pulmonary samples. We compared diagnostic accuracy and reproducibility of urine lipoarabinomannan between point-ofcare readers and laboratory readers. We determined the diagnostic accuracy of individual point-ofcare ultrasound features, performed an external validation of the focused assessment with sonography for HIV/TB (FASH) protocol, and determined independent point-of-care ultrasound predictors of HIV-associated tuberculosis. We derived the decision tree model from multivariable logistic regression models. Results Abdominal ultrasound had a pooled sensitivity of 63% (95%CI 43-79; 5 studies, 368 participants; very low-certainty evidence) and a pooled specificity of 68% (95%CI 42-87; 5 studies, 511 participants; very low-certainty evidence) for bacteriologically confirmed tuberculosis. We screened 556 patients in the cross-sectional study of whom 414 (74.5%) were enrolled. The prevalence of microbiologically confirmed tuberculosis was 41.5% (n=172). Point-of-care and laboratory-performed urine lipoarabinomannan had similar sensitivity (41.8% vs 42.0%, P=1.0) and specificity (90.5% vs 87.5%, P=0.23). Moderate agreement was found between point-of-care and laboratory testing (k=0.62), but there was strong agreement between point-of-care readers (k=0.95) and between laboratory readers (k=0.94). Sensitivity and specificity of ≥1 individual point-of-care ultrasound feature were 73% (95%CI 65-79) and 54% (95%CI 47-60), and of the FASH protocol 71% (95%CI 64-78) and 57% (95%CI 50-63). Independent point-of-care ultrasound predictors identified were intra-abdominal lymphadenopathy of any size (aDOR 3.7; 95%CI 2.0-6.7), ascites (aDOR 3.0; 95%CI 1.5-5.7), and pericardial effusion of any size (aDOR 1.9; 95%CI 1.2-3.0). Two or more independent point-of-care ultrasound predictors had 33% (95%CI 27–41) sensitivity and 91% (95%CI 86-94) specificity. The best performing model included WHO screening symptoms ≥2, antiretroviral therapy use, urinary lipoarabinomannan, independently predictive point-of-care ultrasound features (ascites, any size pericardial effusion, any size intra-abdominal lymphadenopathy), and chest x-ray (c-statistic 0.82; 95%CI 0.78–0.86). Adding CD4 cell count did not improve the performance of the model. Classification And Regression Tree (CART) analysis positioned urinary lipoarabinomannan as the optimal screening test after WHO symptoms (75% true positive rate, representing 17% of participants). Conclusion An evidence-based algorithm for the rapid diagnosis of tuberculosis in HIV-positive patients presenting to an emergency centre was developed. Urinary lipoarabinomannan can be reliably performed at the point-of-care since there was no diagnostic accuracy advantage in laboratory-performed versus pointof-care–performed tests. The role of ultrasound in diagnosing HIV-associated tuberculosis had limitations. The low sensitivity of ultrasound (63% in the systematic review; 73% in the cross-sectional study) and the moderate discrimination (specificity 91%) of the presence of ≥2 independent point-ofcare ultrasound predictors indicate that point-of-care ultrasound results should be interpreted in combination with other diagnostic information. The derived decision tree can facilitate the immediate initiation of anti-tuberculosis treatment in about a quarter of patients among whom 75% would have a definitive diagnosis of tuberculosis regardless of CD4 cell count. The 30% false negative rate indicates that the algorithm should not be used to exclude tuberculosis. The performance of the decision tree needs to be further evaluated in settings with a different prevalence of HIV-associated tuberculosis.
- ItemOpen AccessAnti-retroviral therapy increases the prevalence of dyslipidemia in South African HIV-infected patients(Public Library of Science, 2016) Dave, Joel A; Levitt, Naomi S; Ross, Ian L; Lacerda, Miguel; Maartens, Gary; Blom, DirkPurpose Data on the prevalence of dyslipidaemia and associated risk factors in HIV-infected patients from sub-Saharan Africa is sparse. We performed a cross-sectional analysis in a cohort of HIV-infected South African adults. METHODS: We studied HIV-infected patients who were either antiretroviral therapy (ART)-naive or receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based or protease inhibitor (PI)-based ART. Evaluation included fasting lipograms, oral glucose tolerance tests and clinical anthropometry. Dyslipidemia was defined using the NCEP ATPIII guidelines. RESULTS: The median age of the participants was 34 years (range 19-68 years) and 78% were women. The prevalence of dyslipidemia in 406 ART-naive and 551 participants on ART was 90.0% and 85%, respectively. Low HDL-cholesterol (HDLC) was the most common abnormality [290/406 (71%) ART-naïve and 237/551 (43%) ART- participants]. Participants on ART had higher triglycerides (TG), total cholesterol (TC), LDL-cholesterol (LDLC) and HDLC than the ART-naïve group. Severe dyslipidaemia, (LDLC> 4.9 mmol/L or TG >5.0 mmol/L) was present in <5% of participants. In multivariate analyses there were complex associations between age, gender, type and duration of ART and body composition and LDLC, HDLC and TG, which differed between ART-naïve and ART-participants. CONCLUSION: Participants on ART had higher TG, TC, LDLC and HDLC than those who were ART-naïve but severe lipid abnormalities requiring evaluation and treatment were uncommon.
- ItemOpen AccessAntiretroviral therapy adherence and effectiveness in a private sector disease management programme in Southern Africa(2008) Nachega, Jean B; Maartens, GaryIncludes abstract. Includes bibliographical references.
- ItemOpen AccessAntiretroviral therapy, especially Efavirenz, is associated with low bone mineral density in HIV-infected South Africans(Public Library of Science, 2015) Dave, Joel A; Cohen, Karen; Micklesfield, Lisa K; Maartens, Gary; Levitt, Naomi SPurpose We determined the prevalence and correlates of low bone mineral density (BMD) in HIV-infected South Africans as there is a paucity of such data from Africa. METHODS: BMD and serum 25-hydroxyvitamin D were measured in HIV-positive participants on antiretroviral therapy (ART) and in those not yet on ART (ART-naïve). RESULTS: We enrolled 444 participants [median age 35(IQR: 30, 40) years; 77% women]. BMD was low (z score <-2SD) in 17% and 5% of participants at the lumbar spine and total hip, respectively. Total hip [0.909 (SD 0.123) vs 0.956 (SD 0.124) g/cm 2 , p = 0.0001] and neck of femur BMD [0.796 (SD 0.130) vs 0.844 (SD 0.120) g/cm 2 , p = 0.0001] were lower in the ART, compared to the ART-naïve group. Vitamin D deficiency was present in 15% of participants and was associated with efavirenz use [adjusted OR 2.04 (95% CI 1.01 to 4.13)]. In a multivariate linear regression, exposure to efavirenz or lopinavir-based ART was associated with lower total hip BMD, whereas higher weight, being male and higher vitamin D concentration were associated with higher total hip BMD (adjusted R 2 = 0.28). Age, weight, sex, and the use of efavirenz-based ART were independently associated with lumbar spine BMD (adjusted R 2 = 0.13). CONCLUSIONS: Vitamin D status, use of efavirenz or lopinavir/ritonavir, weight, age and sex are significantly associated with lower BMD in this young cohort of HIV-infected South Africans.
- ItemOpen AccessAntiviral therapy in herpes virus infections(Health and Medical Publishing Group, 2003) Maartens, GaryHerpes viruses are large, enveloped DNA viruses. There are currently 8 known human herpes viruses and 1 primate species that is a rare human pathogen. Most people have been infected with several human herpes viruses. In immunocompetent individuals primary infections with herpes viruses are generally mild, self-limiting infections. After primary infection, herpes viruses remain latent in either sensory nerve ganglia or immune cells. Latency may persist indefinitely unless immune suppression develops, in which case recurrent disease can become life threatening. In the immunocompetent patient, clinical recurrences that are milder than the primary infection are the hallmark of herpes virus infections.
- ItemOpen AccessAssociation of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study(BioMed Central Ltd, 2012) Sinxadi, Phumla; McIlleron, Helen; Dave, Joel; Smith, Peter; Levitt, Naomi; Maartens, GaryBACKGROUND: Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids.AIM:To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults. METHODS: Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. RESULTS: There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) mug/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (beta-coefficient 0.04 (95% CI 0.07 to 0.00)), triglycerides (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), fasting glucose (beta-coefficient 0.01 (95% CI 0.04 to 0.02)), or 2-hour glucose concentrations (beta-coefficient 0.02 (95% CI 0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. CONCLUSIONS: There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.
- ItemOpen AccessAssociation of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study(BioMed Central Ltd, 2012-10-26) Sinxadi, Phumla Z; McIlleron, Helen M; Dave, Joel A; Smith, Peter J; Levitt, Naomi S; Maartens, GaryAbstract Background Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids. Aim To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults. Methods Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. Results There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) μg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (β-coefficient −0.04 (95% CI −0.07 to 0.00)), triglycerides (β-coefficient −0.01 (95% CI −0.04 to 0.02)), fasting glucose (β-coefficient −0.01 (95% CI −0.04 to 0.02)), or 2-hour glucose concentrations (β-coefficient −0.02 (95% CI −0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. Conclusions There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations.
- ItemOpen AccessBaseline Predictors of Sputum Culture Conversion in Pulmonary Tuberculosis: Importance of Cavities, Smoking, Time to Detection and W-Beijing Genotype(Public Library of Science, 2012) Visser, Marianne E; Stead, Michael C; Walzl, Gerhard; Warren, Rob; Schomaker, Michael; Grewal, Harleen M S; Swart, Elizabeth C; Maartens, GaryBACKGROUND: Time to detection (TTD) on automated liquid mycobacterial cultures is an emerging biomarker of tuberculosis outcomes. The M. tuberculosis W-Beijing genotype is spreading globally, indicating a selective advantage. There is a paucity of data on the association between baseline TTD and W-Beijing genotype and tuberculosis outcomes. Aim To assess baseline predictors of failure of sputum culture conversion, within the first 2 months of antitubercular therapy, in participants with pulmonary tuberculosis. Design Between May 2005 and August 2008 we conducted a prospective cohort study of time to sputum culture conversion in ambulatory participants with first episodes of smear and culture positive pulmonary tuberculosis attending two primary care clinics in Cape Town, South Africa. Rifampicin resistance (diagnosed on phenotypic susceptibility testing) was an exclusion criterion. Sputum was collected weekly for 8 weeks for mycobacterial culture on liquid media (BACTEC MGIT 960). Due to missing data, multiple imputation was performed. Time to sputum culture conversion was analysed using a Cox-proportional hazards model. Bayesian model averaging determined the posterior effect probability for each variable. RESULTS: 113 participants were enrolled (30.1% female, 10.5% HIV-infected, 44.2% W-Beijing genotype, and 89% cavities). On Kaplan Meier analysis 50.4% of participants underwent sputum culture conversion by 8 weeks. The following baseline factors were associated with slower sputum culture conversion: TTD (adjusted hazard ratio (aHR) = 1.11, 95% CI 1.02; 1.2), lung cavities (aHR = 0.13, 95% CI 0.02; 0.95), ever smoking (aHR = 0.32, 95% CI 0.1; 1.02) and the W-Beijing genotype (aHR = 0.51, 95% CI 0.25; 1.07). On Bayesian model averaging, posterior probability effects were strong for TTD, lung cavitation and smoking and moderate for W-Beijing genotype. CONCLUSION: We found that baseline TTD, smoking, cavities and W-Beijing genotype were associated with delayed 2 month sputum culture. Larger studies are needed to confirm the relationship between the W-Beijing genotype and sputum culture conversion.
- ItemOpen AccessC-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study(BioMed Central, 2018-08-14) Mendelson, Fiona; Griesel, Rulan; Tiffin, Nicki; Rangaka, Molebogeng; Boulle, Andrew; Mendelson, Marc; Maartens, GaryBackground Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients. Methods We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results. Results Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively). Conclusions CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.
- ItemOpen AccessCases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa(BioMed Central, 2016-11-16) Njuguna, Christine; Swart, Annoesjka; Blockman, Marc; Maartens, Gary; Chisholm, Briony; Stewart, Annemie; Uys, Anri; Cohen, KarenBackground: Gynaecomastia is associated with exposure to antiretroviral therapy (ART), in particular efavirenz. There is limited data on clinical characteristics of patients with ART-associated gynaecomastia in resource-limited settings and little guidance on the optimal management of this adverse drug reaction (ADR). We describe the clinical characteristics, management and outcomes of gynaecomastia cases reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. Methods: We identified all gynaecomastia cases in adolescent boys and men on ART reported to the hotline between June 2013 and July 2014. We collected follow up data telephonically at monthly intervals to document clinical management and outcomes. Results: We received 51 reports of gynaecomastia between June 2013 and July 2014; 11% of the 475 patient-specific ADR queries to the hotline. All patients were on efavirenz-based ART. Mean age was 34 years (standard deviation 12) and seven were adolescents. The median onset of gynaecomastia was 15 months after efavirenz initiation (interquartile range 6–42). Gynaecomastia was bilateral in 29 patients (57%) and unilateral in 16 (31%). Serum testosterone was quantified in 25 of 35 patients with follow up data, and was low in 2 (8%). Efavirenz was replaced with an alternative antiretroviral in 29/35 patients (83%) and gynaecomastia improved in 20/29 (69%). Conclusions: Gynaecomastia was a frequently reported ADR in our setting, occurring with prolonged efavirenz exposure. Testosterone was low in the minority of tested cases. Most clinicians elected to switch patients off efavirenz, and gynaecomastia improved in the majority.
- ItemOpen AccessChanges in blood pressure, glucose levels, insulin secretion and anthropometry after long term exposure to antiretroviral therapy in South African women(2015-08-05) Abrahams, Zulfa; Dave, Joel A; Maartens, Gary; Levitt, Naomi SAbstract Background A number of metabolic abnormalities, such as dysglycaemia, insulin resistance, lipodystrophy and dyslipidaemia, are associated with the use of antiretroviral drugs. We aimed to assess the effects of long-term antiretroviral exposure on blood pressure, glycaemia, insulin secretion and anthropometric measures in black South African women. Methods A convenience sample of HIV-infected women on first-line ART for a median of 16 months at baseline, had the following evaluations twice, at baseline and after approximately 5 years: anthropometry, including skin fold thicknesses, blood pressure, oral glucose test, and insulin. Insulin sensitivity and secretion (HOMA-IR, IGI and DIo) were estimated. Results At baseline more than half the 103 women were using stavudine and efavirenz. The median interval between baseline and follow-up evaluation was 66 months. Weight, waist circumference, and waist-hip ratio increased over time, while limb skinfold thickness decreased over time. Systolic and diastolic blood pressure increased significantly and the proportion of participants with hypertension increased from 3.9 to 15.5% (p < 0.001). There were increases from baseline in plasma glucose concentrations at 30 and 120 min; insulin concentrations at 0 and 30 min; and IGI and DIo. The proportion of participants with diabetes increased from 1 to 7.5% (p = 0.070). Conclusion In black South African women with long-term exposure to ART, increases in hypertension and possibly diabetes were observed. Participants experienced an increase in central fat and a decrease in peripheral fat distribution. Early identification and management of these metabolic changes are important, especially in a region with the highest HIV-infected population in the world.
- ItemOpen AccessClinical and financial burdens of secondary level care in a public sector antiretroviral roll-out setting (G F Jooste Hospital)(Academy of Science of South Africa, 2009) Kevany, Sebastian; Meintjes, Graeme; Rebe, Kevin; Maartens, Gary; Cleary, SusanBackground: Antiretroviral therapy (ART) is being extended across South Africa. While efforts have been made to assess the costs of providing ART via accredited service points, little information is available on its downstream costs, particularly in public secondary level hospitals. Objectives: To determine the cost of care for inpatients and outpatients at a dedicated antiretroviral referral unit treating and caring for antiretroviral-related conditions in a South African peri-urban setting; to identify key epidemiological cost drivers; and to examine the associated clinical and outcome data. Methods: A prospective costing study on 48 outpatients and 25 inpatients was conducted from a health system perspective. Incremental economic costs and clinical data were collected from primary sources at G F Jooste Hospital, Cape Town, over a 1-month period (March 2005). Results: Incremental cost per outpatient was R1 280, and per inpatient R5 802. Costs were dominated by medical staff costs (62% inpatient and 58% outpatient, respectively). Infections predominated among diagnoses and costs – 55% and 67% respectively for inpatients, and 49% and 54% respectively for outpatients. Most inpatients and outpatients were judged by attending physicians to have improved or stabilised as a result of treatment (52% and 59% respectively). Conclusions. The costs of providing secondary level care for patients on or immediately preceding ART initiation can be significant and should be included in the government’s strategic planning: (i) so that the service can be expanded to meet current and future needs; and (ii) to avoid crowding out other secondary level health services.
- ItemOpen AccessClinical characteristics and initial management of patients with tuberculous pericarditis in the HIV era: the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry(BioMed Central Ltd, 2006) Mayosi, Bongani; Wiysonge, Charles; Ntsekhe, Mpiko; Volmink, Jimmy; Gumedze, Freedom; Maartens, Gary; Aje, Akinyemi; Thomas, Baby; Thomas, Kandathil; Awotedu, Abolade; Thembela, Bongani; Mntla, Phindile; Maritz, Frans; Blackett, Kathleen; Nkouonlack,BACKGROUND:The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa. METHODS: Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status. RESULTS: A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs. CONCLUSION: Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.
- ItemOpen AccessClinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors(BioMed Central Ltd, 2010) Pepper, Dominique; Marais, Suzaan; Wilkinson, Robert; Bhaijee, Feriyl; Maartens, Gary; McIlleron, Helen; De Azevedo, Virginia; Cox, Helen; McDermid, Cheryl; Sokhela, Simiso; Patel, Janisha; Meintjes, GraemeBACKGROUND:HIV-1 and Mycobacterium tuberculosis cause substantial morbidity and mortality. Despite the availability of antiretroviral and antituberculosis treatment in Africa, clinical deterioration during antituberculosis treatment remains a frequent reason for hospital admission. We therefore determined the incidence, causes and risk factors for clinical deterioration. METHODS: Prospective cohort study of 292 adults who initiated antituberculosis treatment during a 3-month period. We evaluated those with clinical deterioration over the following 24 weeks of treatment. RESULTS: Seventy-one percent (209/292) of patients were HIV-1 infected (median CD4+: 129 cells/muL [IQR:62-277]). At tuberculosis diagnosis, 23% (34/145) of HIV-1 infected patients qualifying for antiretroviral treatment (ART) were receiving ART; 6 months later, 75% (109/145) had received ART. Within 24 weeks of initiating antituberculosis treatment, 40% (117/292) of patients experienced clinical deterioration due to co-morbid illness (n = 70), tuberculosis related illness (n = 47), non AIDS-defining HIV-1 related infection (n = 25) and AIDS-defining illness (n = 21). Using HIV-1 uninfected patients as the referent group, HIV-1 infected patients had an increasing risk of clinical deterioration as CD4+ counts decreased [CD4+>350 cells/muL: RR = 1.4, 95% CI = 0.7-2.9; CD4+:200-350 cells/muL: RR = 2.0, 95% CI = 1.1-3.6; CD4+<200 cells/muL: RR = 3.0, 95% CI = 1.9-4.7]. During follow-up, 26% (30/117) of patients with clinical deterioration required hospital admission and 15% (17/117) died. Fifteen deaths were in HIV-1 infected patients with a CD4+<200 cells/muL. CONCLUSIONS: In multivariate analysis, HIV-1 infection and a low CD4+ count at tuberculosis diagnosis were significant risk factors for clinical deterioration and death. The initiation of ART at a CD4+ count of <350 cells/muL will likely reduce the high burden of clinical deterioration.
- ItemOpen AccessComparison of six methods to estimate adherence in an ART-naïve cohort in a resource-poor setting: which best predicts virological and resistance outcomes?(BioMed Central, 2017-04-04) Orrell, Catherine; Cohen, Karen; Leisegang, Rory; Bangsberg, David R; Wood, Robin; Maartens, GaryBackground: Incomplete adherence to antiretroviral therapy (ART) results in virologic failure and resistance. It remains unclear which adherence measure best predicts these outcomes. We compared six patient-reported and objective adherence measures in one ART-naïve cohort in South Africa. Methods: We recruited 230 participants from a community ART clinic and prospectively collected demographic data, CD4 count and HIV-RNA at weeks 0, 16 and 48. We quantified adherence using 3-day self-report (SR), clinicbased pill count (CPC), average adherence by pharmacy refill (PR-average), calculation of medication-free days (PR-gaps), efavirenz therapeutic drug monitoring (TDM) and an electronic adherence monitoring device (EAMD). Associations between adherence measures and virologic and genotypic outcomes were modelled using logistic regression, with the area under the curve (AUC) from the receiver operator characteristic (ROC) analyses derived to assess performance of adherence measures in predicting outcomes. Results: At week 48 median (IQR) adherence was: SR 100% (100–100), CPC 100% (95–107), PR-average 103% (95– 105), PR-gaps 100% (95–100) and EAMD 86% (59–94), and efavirenz concentrations were therapeutic (>1 mg/L) in 92%. EAMD, PR-average, PR-gaps and CPC best predicted virological outcome at week 48 with AUC ROC of 0.73 (95% CI 0.61–0.83), 0.73 (95% CI 0.61–0.85), 0.72 (95% CI 0.59–0.84) and 0.64 (95% CI 0.52–0.76) respectively. EAMD, PR-gaps and PR-average were highly predictive of detection of resistance mutations at week 48, with AUC ROC of 0.92 (95% CI 0.87–0.97), 0.86 (0.67–1.0) and 0.83 (95% CI 0.65–1.0) respectively. SR and TDM were poorly predictive of outcomes at week 48. Conclusion: EAMD and both PR measures predicted resistance and virological failure similarly. Pharmacy refill data is a pragmatic adherence measure in resource-limited settings where electronic monitoring is unavailable. Trial registration The trial was retrospectively registered in the Pan African Clinical Trials Registry, number PACTR201311000641402, on the 13 Sep 2013 (www.pactr.org). The first participant was enrolled on the 12th July 2012. The last patient last visit (week 48) was 15 April 2014
- 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 AccessCorrection to: Diagnostic accuracy of the Xpert MTB/Rif Ultra for tuberculosis adenitis(2020-03-02) Antel, Katherine; Oosthuizen, Jenna; Malherbe, Francois; Louw, Vernon J; Nicol, Mark P; Maartens, Gary; Verburgh, EstelleAfter publication of the original article [1], we were notified that there is a mistake in the article note.
- ItemOpen AccessCost-effectiveness of highly active antiretroviral therapy in South Africa(Public Library of Science, 2005) Badri, Motasim; Maartens, Gary; Mandalia, Sundhiya; Bekker, Linda-Gail; Penrod, John R; Platt, Robert W; Wood, Robin; Beck, Eduard JHealthcare costs for HIV-infected South African adults on HAART compared with costs for HIV-infected controls not on HAART. Authors conclude HAART is cost effective.