Browsing by Author "Muller, Daniel"

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    Antiretroviral concentration measurements as an additional tool to manage virologic failure in resource limited settings: a case control study
    (AIDS research and therapy, 2019) Buzibye, Allan; Musaazi, Joseph; Braun, Amrei von; Nanzigu, Sarah; Sekaggya‑Wiltshire, Christine; Kambugu, Andrew; Fehr, Jan; Lamorde, Mohammed; Gutteck, Ursula; Muller, Daniel; Sowinski, Stefanie; Reynolds, Steven J.; Castelnuovo, Barbara
    Several studies demonstrate a correlation between sub-therapeutic concentrations of antiretroviral drugs and virologic failure. We examined the sensitivity, specificity and predictive values of sub-therapeutic drug levels in predicting viralogic failure. Methods: This was a case control study with cases being samples of participants with virologic failure, and controls samples of participants with virologic suppression. We analyzed samples obtained from participants that had been on antiretroviral treatment (ART) for at least 6 months. Virologic failure was defined as HIV-RNA viral load ≥ 1000 copies/ ml. Sub-therapeutic drug levels were defined according to published reference cutoffs. The diagnostic validity of drug levels for virologic failure was assessed using plasma viral loads as a gold standard. Results: Sub-therapeutic ART concentrations explained only 38.2% of virologic failure with a probability of experiencing virologic failure of 0.66 in a patient with low drug levels versus 0.25 for participants with measurements within or above the normal range. Approximately 90% of participants with ART concentrations above the lower clinical cut off did not have virologic failure. Conclusions: These results support prior indication for therapeutic drug monitoring in cases of suspected virologic failure.
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    Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study
    (BMJ open, 2017) Sekaggya-Wiltshire, Christine; Castelnuovo, Barbara; Braun, Amrei von; Musaazi, Joseph; Muller, Daniel; Buzibye, Allan; Gutteck, Ursula; Henning, Lars; Ledergerber, Bruno; Corti, Natascia; Lamorde, Mohammed; Fehr, Jan; Kambugu, Andrew
    Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. Participants Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on firstline anti-TB treatment. Findings to date Between April 2013 and April 2015, the cohort enrolled 268 patients coinfected with TB/HIV ; 57.8% are male with a median age of 34 years (IQR 29–40). The median time between the diagnosis of HIV and the diagnosis of TB is 2 months (IQR 0–22.5). The majority of the patients are antiretroviral therapy naive (75.4%). Our population is severely immunosuppressed with a median CD4 cell count at enrolment of 163 cells/μL (IQR 46–298). Ninety-nine per cent of the patients had a diagnosis of pulmonary TB confirmed by sputum microscopy, Xpert/RIF or culture and 203 (75.7%) have completed TB treatment with 5099 aliquots of blood collected for pharmacokinetic analysis. Future plans This cohort provides a large database of well-characterised patients coinfected with TB/HIV which will facilitate the description of the association between serum drug concentrations and TB treatment outcomes as well as provide a research platform for future substudies including evaluation of virological outcomes.
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    Delayed Sputum Culture Conversion in Tuberculosis– Human Immunodeficiency Virus–Coinfected Patients With Low Isoniazid and Rifampicin Concentrations
    (Clinical Infectious Diseases, 2018) Sekaggya-Wiltshire, Christine; Braun, Amrei von; Lamorde, Mohammed; Ledergerber, Bruno; Buzibye, Allan; Henning, Lars; Musaazi, Joseph; Gutteck, Ursula; Denti, Paolo; Kock, Miné de; Jetter, Alexander; Byakika-Kibwika, Pauline; Eberhard, Nadia; Matovu, Joshua; Joloba, Moses; Muller, Daniel; Manabe, Yukari C.; Kamya, Moses R.; Corti, Natascia; Kambugu, Andrew; Castelnuovo, Barbara; Fehr2, Jan S.
    The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods. We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results. We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37–.77; P = .001) or by the end of follow-up (0.61; .44–.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion. Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission.
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    Low Antituberculosis Drug Concentrations in HIV-Tuberculosis- Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?
    (Antimicrob Agents Chemother, 2019) Sekaggya-Wiltshire, Christine; Chirehwa, Maxwell; Musaazi, Joseph; Braun, Amrei von; Buzibye, Allan; Muller, Daniel; Gutteck, Ursula; Motta, Ilaria; Calcagno, Andrea; Fehr, Jan S.; Kambugu, Andrew; Castelnuovo, Barbara; Lamorde, Mohammed; Denti, Paolo
    Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing 55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)