Browsing by Author "Henning, Lars"

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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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    If It Looks Like a Duck, Swims Like a Duck, and Quacks Like a Duck—Does It Have to Be a Duck?
    (Neglected Tropical Diseases, 2016) Nalwanga, Damalie; Henning, Lars
    On 2nd July 2013, a 29-year-old HIV-positive woman presented herself to the outpatient clinic at the Infectious Diseases Institute in Kampala, Uganda. Her weight had decreased from 46 kg to 42 kg in the past few weeks. In addition, she complained about abdominal pain, diarrhea, vomiting, and evening fevers during the week leading up to her visit (see Table 1 and Fig 1 for patient characteristics). Her CD4 T cell count in June 2013 was 34 cells/μl, and she had documented second-line antiretroviral treatment (tenofovir disoproxil fumarate, emtricitabine, and lopinavir-ritonavir) failure. She admitted to taking her medications irregularly and was on tri methoprim-sulfamethoxazole prophylaxis. Her last HIV-1 RNA viral load in June 2013 was 199,994 copies/ml. Based on her immunosuppression and symptoms, we screened her for tuberculosis (TB). At the time of screening, she could not produce sputum, but an abdominal ultrasound in late June 2013 showed a lymphadenopathy. A chest X-ray was not carried out at baseline, as it would not have changed the clinical decision to treat the presumptive diagnosis of extrapulmonary TB. Her glomerular filtration rate (GFR) was 55 mL/min, the liver enzyme alanine aminotransferase was 33 IU/L (normal range 0–35 IU/L), and her albumin level was slightly decreased (35.5 g/L; normal range 38–47 g/L).
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    Low isoniazid and rifampicin concentrations in TB/HIV co-infected patients in Uganda
    (Journal of the International AIDS Society, 2014) Sekaggya Wiltshire, Christine; Lamorde, Mohammed; Scherrer, Alexandra; Musaazi, Joseph; Corti, Natascia; Allan, Buzibye; Nakijoba, Rita; Nalwanga, Damalie; Henning, Lars; Von Braun, Amrei; Okware, Solome; Kambugu, Andrew; Fehr, Jan; Castelnuovo, Barbara
    There is limited data available on exposure to anti-tuberculosis (TB) drugs in this region. Peloquin has described reference ranges [1] however some studies have demonstrated that patients actually achieve concentrations below these ranges [2]. There is limited data about exposure to anti-TB drugs in the HIV/TB co-infected population in Sub-Saharan Africa. Our objective is to describe the concentration of anti-TB drug levels in a well characterized prospective cohort of adult patients starting treatment for pulmonary TB. Methods: This study is an ongoing study carried out in the TB/HIV integrated clinic at the Infectious Diseases Institute in Kampala, Uganda. Sputum culture and microscopy was done for all patients. We performed pharmacokinetic blood sampling of anti-TB drugs for 1 hour, 2 hours and 4 hours post dose at 2 weeks, 8 weeks and 24 weeks after initiation of anti-TB treatment using ultraviolet high-performance liquid chromatography (UV-HPLC). We described the maximum concentration (Cmax) of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) and compare them with the values observed by Peloquin et al. referenced in other studies. Results: We started 113 HIV infected adults on a fixed dose combination of HREZ. The median age of our population was 33 years, of which 52% were male with a median BMI of 19 kg/m2 and a median CD4 cell count of 142 cells/mL. In 90% of the participants, the diagnosis of TB was based on microscopy and or cultures. The boxplot graph shows the median Cmax and IQR of H and R. Levels of H were found to be below the reference ranges (3 6 mg/mL) in 54/77(70.1%), 38/59(64.4%) and 15/24(62.5%) participants at weeks 2, 8 and 24. Rif levels were also found to be below the reference ranges (8 24 mg/mL) in 41/66(62.1%), 26/48(54.2%) and 8/10(8%) participants at weeks 2, 8 and 24, respectively. The mean Cmax of E and Z were within the reference range at week 2 and 8; mean Cmax of 3.29SD2.1 mg/mL and 4.09SD3.1 mg/mL for E and 41.69SD13.1 mg/mL and 42.69SD16.4 mg/mL for Z. Conclusion: We observed lower concentrations of isoniazid and rifampicin in our study population of HIV/TB co-infected patients. The implications of these findings are not yet clear.We therefore need to correlate our findings with the response to TB treatment.