Research Spotlight

Pasipanodya, J. G., W. Smythe, C. S. Merle, P. L. Olliaro, D. Deshpande, G. Magombedze, H. McIlleron and T. Gumbo (2018). “Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.” Clin Infect Dis 67(suppl_3): S284-s292.

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Background: In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic (PK) study. We sought to determine if PK variability played a role in patient outcomes. Methods: Patients recruited in the trial were followed for 24 months, and relapse ascertained using spoligotyping. Blood was drawn for drug concentrations on 2 separate days during the first 2 months of therapy, and compartmental PK analyses was performed. Failure to attain sustained sputum culture conversion at the end of treatment, relapse, or death during follow-up defined therapy failure. In addition to standard statistical analyses, we utilized an ensemble of machine-learning methods to identify patterns and predictors of therapy failure from among 27 clinical and laboratory features. Results: Of 126 patients, 95 (75%) had favorable outcomes and 19 (15%) failed therapy, relapsed, or died. Pyrazinamide and rifampicin peak concentrations and area under the concentration-time curves (AUCs) were ranked higher (more important) than gatifloxacin AUCs. The distribution of individual drug concentrations and their ranking varied significantly between South African and West African trial sites; however, drug concentrations still accounted for 31% and 75% of variance of outcomes, respectively. We identified a 3-way antagonistic interaction of pyrazinamide, gatifloxacin, and rifampicin concentrations. These negative interactions disappeared if rifampicin peak concentration was above 7 mg/L. Conclusions: Concentration-dependent antagonism contributed to death, relapse, and therapy failure but was abrogated by high rifampicin concentrations. Therefore, increasing both rifampin and gatifloxacin doses could improve outcomes. Clinical Trials Registration: NCT002216385.

O’Brien, A., P. S. Kamath and J. Trotter (2018). “MACHT – Outpatient albumin infusions do not prevent complications of cirrhosis in patients on the liver transplant waiting list.” J Hepatol 69(6): 1217-1218.

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Albumin has long been an important option in the treatment of patients with cirrhosis and ascites. Albumin improves circulatory function; and is widely recommended for use in inpatients with cirrhosis complicated by hepatorenal syndrome and spontaneous bacterial peritonitis, as well as to prevent post paracentesis circulatory dysfunction following large volume paracentesis (LVP). Albumin has beneficial immunomodulatory and endothelial effects.5 Therefore, many centres use albumin as an unproven, but seemingly effective agent as an adjuvant to chronic diuretic therapy for ascites in patients with cirrhosis. In particular, patients regarded to have the greatest potential benefit are those with chronic renal insufficiency who tolerate diuretic therapy poorly. Midodrine, an α‐adrenergic agonist, has been shown to improve systemic and renal hemodynamics in patients with ascites. However, a meta‐analysis of 10 trials using midodrine to treat ascites showed no beneficial effect on survival and when used as an alternative to albumin in LVP, the mortality was higher for midodrine than albumin. Furthermore, the addition of the somatostatin analogue, octreotide to midodrine was not superior to albumin in preventing ascites recurrence compared to albumin. In the current issue of this Journal, Sola et al. report on the MACHT trial (midodrine and albumin for cirrhotic patients in the waiting list for liver transplantation) conducted by the centre with the best record of performing clinically important trials in advanced liver disease. This study showed that in patients with cirrhosis awaiting liver transplantation, outpatient treatment with midodrine and albumin (40 g every 2 weeks) slightly suppressed the vasoconstrictor activity, but neither prevented complications of cirrhosis nor improved survival. This was a double blinded placebo-controlled trial using opaque bags and intravenous sets to administer albumin or placebo. However, only 9 patients were treated for the entire year, the median length of treatment was actually only 80 days and the mortality rate in both arms was very low. This demonstrates how challenging these studies are, in particular “natural history” studies in liver transplant candidates as transplantation frequently interrupts the course of the patients’ disease. Therefore, the results of this important study should be considered in light of these qualifications. (Excerpt from this commentary on the MACHT trial, p. 1217; no abstract available.)

Nadler, E., S. Joo, M. Boyd, J. Black-Shinn and D. Chirovsky (2018). “Treatment patterns and outcomes among patients with recurrent/metastatic squamous cell carcinoma of the head and neck.” Future Oncol Dec 4. [Epub ahead of print].

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AIM: Cetuximab was approved in 2008 for treating recurrent/metastatic (R/M) head-and-neck squamous-cell carcinoma (HNSCC), and this study assessed the utilization of cetuximab for R/M-HNSCC in a real-world setting. MATERIALS & METHODS: Adult patients with R/M-HNSCC, who initiated systemic therapy between 1 September 2011 and 31 December 2014 and followed through 31 December 2015, were identified from iKnowMed electronic-health-records database (McKesson Specialty Health) supplemented with manual chart-abstraction. RESULTS: For 325 R/M-HNSCC patients; median age 62 years; 82% males, 67% had oropharyngeal cancer, most common first-line (1L) regimen was platinum-based combinations (76%), of whom only 8% received platinum + cetuximab +/- 5 fluorouracil. CONCLUSION: Despite US FDA approval and National Comprehensive Cancer Network guidelines recommending use of cetuximab for palliative treatment of R/M-HNSCC, our study demonstrates low utilization in 1L and 2L settings, underscoring the need to understand reasons for low utilization.E

Meeuwis, K. A. P., A. Potts Bleakman, P. C. M. van de Kerkhof, Y. Dutronc, C. Henneges, L. J. Kornberg and A. Menter (2018). “Prevalence of genital psoriasis in patients with psoriasis.” J Dermatolog Treat 29(8): 754-760.

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BACKGROUND: Psoriatic lesions in the genital area (GenPs) can cause considerable physical and emotional distress. To increase physician awareness, we estimated the GenPs prevalence among patients with psoriasis. METHODS: An English language literature search was performed. Articles reporting GenPs prevalence met the search criteria and were included. Because GenPs is rarely reported in demographics of prospective clinical trials, GenPs prevalence and baseline demographics of patients with and without GenPs in two prospective randomized phase 3b trials (NCT02561806 and NCT02634801) involving patients with moderate-to-severe psoriasis are reported. RESULTS: Overall, 600 references were screened. Eighteen articles met the search criteria. Patient populations were highly heterogeneous across articles. Broadly, the presence of GenPs was either physician-reported (physical examinations) or patient-reported (questionnaires). In the literature, GenPs prevalence at the time of reporting ranged from 7% to 42% and the prevalence of GenPs at any time during the course of psoriasis ranged from 33% to 63%. In the two prospective clinical trials, the prevalence of GenPs at the time of enrollment was 35-42%. CONCLUSION: A substantial proportion of patients experience genital lesions at some time during the course of psoriasis. Increased awareness of GenPs prevalence may drive improved assessment and treatment.

Magombedze, G., J. G. Pasipanodya, S. Srivastava, D. Deshpande, M. E. Visser, E. Chigutsa, H. McIlleron and T. Gumbo (2018). “Transformation Morphisms and Time-to-Extinction Analysis That Map Therapy Duration From Preclinical Models to Patients With Tuberculosis: Translating From Apples to Oranges.” Clin Infect Dis 67(suppl_3): S349-s358.

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Background: A major challenge in medicine is translation of preclinical model findings to humans, especially therapy duration. One major example is recent shorter-duration therapy regimen failures in tuberculosis. Methods: We used set theory mapping to develop a computational/modeling framework to map the time it takes to extinguish the Mycobacterium tuberculosis population on chemotherapy from multiple hollow fiber system model of tuberculosis (HFS-TB) experiments to that observed in patients. The predictive accuracy of the derived translation transformations was then tested using data from 108 HFS-TB Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) units, including 756 colony-forming units (CFU)/mL. Derived transformations, and Latin hypercube sampling-guided simulations were used to predict cure and relapse after 4 and 6 months of therapy. Outcomes were compared to observations, in 1932 patients in the REMoxTB clinical trial. Results: HFS-TB serial bacillary burden and serial sputum data in the derivation dataset formed a structure-preserving map. Bactericidal effect was mapped with a single step transformation, while the sterilizing effect was mapped with a 3-step transformation function. Using the HFS-TB REMoxTB data, we accurately predicted the proportion of patients cured in the 4-month REMoxTB clinical trial. Model-predicted vs clinical trial observations were (i) the ethambutol arm (77.0% [95% confidence interval {CI}, 74.4%-79.6%] vs 77.7% [95% CI, 74.3%-80.9%]) and (ii) the isoniazid arm (76.4% [95% CI, 73.9%-79.0%] vs 79.5% [95% CI, 76.1%-82.5%]). Conclusions: We developed a method to translate duration of therapy outcomes from preclinical models to tuberculosis patients.