Browsing by Author "Maartens Gary"

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    A randomised controlled trial of N-acetylcysteine in the management of anti-tuberculosis drug-induced liver injury
    (2023) Moosa, Muhammed; Cohen, Karen; Maartens Gary
    Background: Liver injury is the most common severe adverse effect of first-line anti-tuberculosis therapy (ATT). Nacetylcysteine (NAC) has efficacy in patients with paracetamol toxicity, and may be of benefit in liver injury due to other causes, such as ATT-induced liver injury (AT-DILI). Rechallenge of first line ATT after liver injury is usually attempted and may result in recurrence of liver injury. Alanine transaminase (ALT) is the biomarker currently used in AT-DILI diagnosis. MicroRNA-122 (miR-122) is a sensitive biomarker for liver injury due to paracetamol, but data on utility as a biomarker for ATDILI are limited. Methods: We conducted a randomized double-blind placebo-controlled trial of intravenous NAC in adult hospitalized participants with AT-DILI. Primary endpoint was time to ALT < 100 U/L; secondary endpoints included length of hospital stay and 8-week mortality. We described outcomes of ATT rechallenge following AT-DILI. We quantified miR-122 and ALT concentrations before and after infusion of NAC/placebo, and explored the effect of NAC on miR-122. Results We enrolled 102 participants with AT-DILI, 53 randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV positive. Median time to ALT
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    Clinical, pharmacokinetic, and genetic determinants of change in serum creatinine among Southern Africans on dolutegravir based antiretroviral therapy
    (2023) Mpofu, Rephaim; Sinxadi, Phumla; Maartens Gary
    Introduction: Dolutegravir increases serum creatinine by inhibiting renal secretion of creatinine, potentially resulting in inappropriate regimen switches. We investigated determinants of early changes in serum creatinine in a Southern African cohort starting dolutegravir-based antiretroviral therapy. Methods: We conducted a secondary analysis of data from participants in a randomised controlled trial of dolutegravir with tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) plus emtricitabine (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic, and genetic factors associated with the change in serum creatinine from baseline to week 4 using linear regression adjusting for age, sex, baseline serum creatinine, HIV-1 RNA viral load, CD4 T-cell count, total body weight, and co-trimoxazole use. Results: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 µmol.L-1. Dolutegravir area under the 24-hour concentration-time curve (change in creatinine regression coefficient [β] = 2.78 [95% confidence interval 0.54, 5.01]) and male sex (β = 5.20 [2.92, 7.48]) were associated with an increased change in serum creatinine at week 4, while higher baseline serum creatinine (β = -0.22 [-0.31, -0.12]), use of TAF (β = -2.30 [-4.06, -0.53]) and Uridine glucuronosyltransferase 1A1 (UGT1A1) polymorphism rs929596 (β = -2.33 [-4.49, -0.17]; not significant after adjustment for multiple comparisons) were associated with a decreased change in serum creatinine. Conclusion: We identified clinical and pharmacokinetic determinants of change in serum creatinine in participants starting a dolutegravir-based regimen. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.
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    Effect of dihydroartemisin-piperaquine for malaria intermittent preventive treatment on dolutegravir exposure in pregnant women living with HIV
    (2023) Banda, Clifford; Barnes, Karen; Maartens Gary
    Background: In sub-Saharan Africa, the disease burden of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PWLHIV) require both antiretroviral therapy and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin-piperaquine has been identified as a promising alternative to sulfadoxine-pyrimethamine for malaria prevention in pregnancy. However, another antimalarial drug, artesunate-amodiaquine, similar to dihydroartemisininpiperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults. Objective: To investigate the effect of dihydroartemisinin-piperaquine for IPTp on dolutegravir plasma exposure in pregnant women on dolutegravir-based antiretroviral therapy. Methods: We conducted an open-label, non-randomised, fixed sequence, pharmacokinetic study in PWLHIV in Malawi. Dolutegravir concentrations were measured over a 24-hour period, before and after the recommended three-day treatment dose of dihydroartemisininpiperaquine in 12 pregnant women in their 2nd or 3rd trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods. Results: Co-administration of dihydroartemisinin-piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24hr) and maximum concentration (Cmax) by 30% (GMR,1.30; 90% CI, 1.11-1.52) and 31% (GMR, 1.31; 90% CI,1.13-1.51), respectively. Furthermore, dolutegravir's trough (C24) concentration increased by 42% (GMR,1.42; 90% CI,1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed. Conclusion: Dihydroartemisinin-piperaquine may be administered as IPTp with dolutegravir-based antiretroviral therapy in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, assures its efficacy without any clinically significant adverse events observed in this small study
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    Pharmacometrics of dolutegravir and tenofovir: a quantitative approach to characterise drug-drug interactions, pharmacogenetics and optimise treatment
    (2023) Kawuma, Aida; Denti, Paolo; Maartens Gary
    Africa houses more than 50% of the 37 million people estimated to be living with HIV (PLWH). Although great strides have been made in increasing access to antiretroviral therapy, the number of new HIV infections remains high. In sub-Saharan Africa, co-infections of HIV, tuberculosis, and malaria are common because the three pandemics overlap considerably. Treatment of these co-infections is often challenging because of the potential for drug-drug interactions. Dolutegravir-based regimens are now the preferred first-line option for the management of HIV. Therefore, many African countries have transitioned most PLWH from efavirenz- to dolutegravir-based regimens. A fixed-dose combination containing dolutegravir, tenofovir, and lamivudine taken daily constitutes one of the most widely used regimens in Africa. In this thesis, we employ population pharmacokinetic modelling to optimise HIV treatment using data from healthy volunteers or PLWH, some of whom also have tuberculosis. We characterise dolutegravir pharmacokinetics, pharmacogenetics, and its drug-drug interaction with the antituberculosis drugs rifampicin and rifabutin and with the antimalarial drugs artemether-lumefantrine and artesunate-amodiaquine. We also describe the pharmacokinetics of tenofovir when dosed as either tenofovir disoproxil fumarate or tenofovir alafenamide in South Africans living with HIV. We found that rifampicin increases dolutegravir clearance more than twofold, leading to a reduction in its exposure. We confirmed that this interaction can be overcome with twice-daily dosing of 50-mg dolutegravir. We also demonstrate that a simpler regimen of 100 mg once daily may be sufficient. We also found that rifabutin decreases dolutegravir volume of distribution, but without an overall change in exposure. The interaction between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine was not clinically significant, and no dose adjustment is required when these are co-administered. Lastly, we demonstrate that polymorphisms within the UGT1A locus affect dolutegravir exposure among Africans. For tenofovir, we created a joint model that describes its disposition when given either as tenofovir disoproxil fumarate or tenofovir alafenamide. In conclusion, by employing pharmacometric techniques, we were able to analyze and pool data from different studies, including sparsely sampled data, and run simulations to test and inform alternative dosing scenarios.
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    The development, validation, and evaluation of quantitative assays for determining adherence of heart failure patients to carvedilol, enalapril and perindopril
    (2023) Joubert, André; Wiesner, Joachim; Maartens Gary
    Background: Heart failure (HF) is a global pandemic with a rising prevalence rate in low- and middle-income countries (LMICs). Poor medication adherence contributes to the impact of chronic diseases such as HF. However, there are sparse adherence data on HF patients in sub-Saharan Africa (SSA). This is problematic as African HF patients have a high mortality rate, which is poorly understood. Poor medication adherence could contribute to the high mortality rate of African HF patients. Objective adherence measures are better than subjective measures (for example, patient recall) at predicting outcomes. In addition, the adherence method should be applicable to resource-scarce settings. Novel multiplex assays were developed to quantify carvedilol, enalaprilat and perindoprilat in dried blood spots (DBS) and correlated with plasma. Carvedilol, enalapril and perindopril are medications commonly used to treat HF, with enalaprilat and perindoprilat being the active metabolites of enalapril and perindopril, respectively. The developed assays were then evaluated in terms of their ability to discern between non-adherent and adherent patients and their suitability for use in resource-scarce settings. Method: The DBS and plasma assays were validated per the United States Food and Drug Administration (FDA) guidelines. The plasma assay was validated over a calibration range of 0.2–200 ng/mL for carvedilol, enalaprilat and perindoprilat. The DBS assay was validated over a range of 1.00–200 ng/mL for the three analytes. The DBS assays were correlated with plasma concentrations in a pilot intensive pharmacokinetic study of six patients. The correlation was determined using Deming regression, with Bland–Altman analysis used to establish agreement between observed and calculated plasma concentrations. Calculated plasma concentrations were obtained using the Deming regression equations describing the relationship between DBS and plasma concentrations. Results: Accuracy, precision, selectivity and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested for both assays. Stability of the analytes in the matrix and throughout sample processing was proven for both assays. The full range of plasma pharmacokinetic samples could be quantified for all analytes, with the lower limit of quantification (LLOQ) of 0.2 ng/mL proving to be sufficient. The pharmacokinetic pilot study's full range of DBS concentrations could be quantified for enalaprilat but not for carvedilol and perindoprilat. The LLOQ of 1.00 ng/mL was not sensitive enough to quantify the lowest concentrations of some patients for these two analytes. Good correlations were observed between DBS and plasma pharmacokinetic samples, with the Pearson's correlation coefficient (r) greater than 0.94 for all analytes. The difference between the observed and calculated plasma concentrations was less than 20% of their mean for > 67% of samples for all analytes, indicating good agreement between observed and calculated plasma concentrations for all analytes. Conclusions: The plasma assay is suited for evaluating patient adherence to carvedilol, enalapril and perindopril medication. The assay is robust and sensitive enough to discern between those who are adherent and non-adherent. Due to the wealth of pharmacokinetic data available for the analytes in plasma, through pharmacokinetic modelling, it is possible to determine the most appropriate dose and weight-specific adherence interpretation for that patient rather than relying on a general cut-off value. In other words, adherence interpretation can be individualised based on a patient's own dose and weight. Plasma as a matrix, however, is not very amenable to resource-scarce settings. The matrix requires strict storage and transport conditions, so creating additional logistic difficulties and expenses in resource-scarce and remote locations. These are difficulties that would have to be accommodated to use the assay. It was found that the DBS assay is more suitable as a screening assay for carvedilol and perindoprilat than as an assay to gauge adherence. The assay is suitable as an adherence determining assay for enalaprilat, however. The prolonged terminal half-life of enalaprilat allows sufficient DBS concentrations to track adherence. The DBS assay's higher LLOQ and the higher concentration of the analytes in plasma versus that of whole blood places the assay at a stark disadvantage in terms of sensitivity relative to the plasma assay. DBS samples have a significant advantage over plasma samples in their less stringent storage and transport requirements. As a matrix, DBS is far more conducive to remote and resource-scarce areas when compared to plasma. The robustness of both assays was proven with cross-validation using actual clinical samples. Good agreement between observed and calculated plasma concentrations means that DBS concentrations, once normalised, can be used interchangeably with plasma samples. DBS samples can be collected at the sampling sites, taking advantage of the DBS matrix's less stringent storage and transportation requirements. Once the samples are analysed, the concentrations can be converted to plasma concentrations, which can be interpreted more efficiently in terms of adherence. However, this would only be feasible for enalaprilat, as the DBS assay for the carvedilol and perindoprilat analytes lacked sensitivity to reflect ingestion within the last 24 hours.