| 1. |
- Karat, Aaron S., et al.
(författare)
-
Measuring mortality due to HIV-associated tuberculosis among adults in South Africa : Comparing verbal autopsy, minimally-invasive autopsy, and research data
- 2017
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
-
Tidskriftsartikel (refereegranskat)abstract
- Background The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases (ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA). Methods and findings Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range [IQR] 33-47) years and CD4 count 51 (IQR 22-102) cells/mu L. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance [CCC] 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively). Conclusions Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.
|
|
| 2. |
- Karat, Aaron S., et al.
(författare)
-
Performance of verbal autopsy methods in estimating HIV-associated mortality among adults in South Africa
- 2018
-
Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 3:4
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Verbal autopsy (VA) can be integrated into civil registration and vital statistics systems, but its accuracy in determining HIV-associated causes of death (CoD) is uncertain. We assessed the sensitivity and specificity of VA questions in determining HIV status and antiretroviral therapy (ART) initiation and compared HIV-associated mortality fractions assigned by different VA interpretation methods.Methods: Using the WHO 2012 instrument with added ART questions, VA was conducted for deaths among adults with known HIV status (356 HIV positive and 103 HIV negative) in South Africa. CoD were assigned using physician-certified VA (PCVA) and computer-coded VA (CCVA) methods and compared with documented HIV status.Results: The sensitivity of VA questions in detecting HIV status and ART initiation was 84.3% (95% CI 80 to 88) and 91.0% (95% CI 86 to 95); 283/356 (79.5%) HIV-positive individuals were assigned HIV-associated CoD by PCVA, 166 (46.6%) by InterVA-4.03, 201 (56.5%) by InterVA-5, and 80 (22.5%) and 289 (81.2%) by SmartVA-Analyze V.1.1.1 and V.1.2.1. Agreement between PCVA and older CCVA methods was poor (chance-corrected concordance [CCC] <0; cause-specific mortality fraction [CSMF] accuracy <= 56%) but better between PCVA and updated methods (CCC 0.21-0.75; CSMF accuracy 65%-98%). All methods were specific (specificity 87% to 96%) in assigning HIV-associated CoD.Conclusion: All CCVA interpretation methods underestimated the HIV-associated mortality fraction compared with PCVA; InterVA-5 and SmartVA-Analyze V. 1.2.1 performed better than earlier versions. Changes to VA methods and classification systems are needed to track progress towards targets for reducing HIV-associated mortality.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Litjens, Carlijn H. C., et al.
(författare)
-
Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
-
Tidskriftsartikel (refereegranskat)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
|
|
| 6. |
- Maraba, Noriah, et al.
(författare)
-
Verbal autopsy-assigned causes of death among adults being investigated for TB in South Africa
- 2016
-
Ingår i: Transactions of the Royal Society of Tropical Medicine and Hygiene. - : Oxford University Press. - 0035-9203 .- 1878-3503. ; 110:9, s. 510-516
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Adults being investigated for TB in South Africa experience high mortality, yet causes of death (CoD) are not well defined. We determined CoD in this population using verbal autopsy (VA), and compared HIV- and TB-associated CoD using physician-certified verbal autopsy (PCVA) and InterVA-4 software. Methods: All contactable consenting caregivers of participants who died during a trial comparing Xpert MTB/RIF to smear microscopy were interviewed using the WHO VA tool. CoD were assigned using PCVA and InterVA-4. Kappa statistic (K) and concordance correlation coefficient (CCC) were calculated for comparison. Results: Among 231 deaths, relatives of 137 deceased were interviewed. Of the 137 deceased 76 (55.4%) were males, median age 41 years (IQR 33-50). PCVA assigned 70 (51.1%) TB immediate CoD (44 [62.8%] pulmonary TB; 26 [37.1%] extra-pulmonary TB); 21 (15.3%) HIV/AIDS-related; and 46 (33.5%) other CoD. InterVA-4 assigned 48 (35.0%) TB deaths; 49 (35.7%) HIV/AIDS-related deaths; and 40 (29.1%) other CoD. Agreement between PCVA and InterVA-4 CoD was slight at individual level (K=0.20; 95% CI 0.10-0.30) and poor at population level (CCC 0.67; 95% CI 0.38-0.99). Conclusions: TB and HIV are leading CoD among adults being investigated for TB. PCVA and InterVA agreement at individual level was slight and poor at population level. VA methodology needs further development where TB and HIV are common.
|
|
| 7. |
- Zvada, Simbarashe P., et al.
(författare)
-
Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients
- 2014
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 58:1, s. 503-510
-
Tidskriftsartikel (refereegranskat)abstract
- Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC(0-24)) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC(0-24)/MIC ratios of >= 53 and >= 100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >= 53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >= 100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.
|
|
