Infectious Disease

Shang, M., J. R. Chung, M. L. Jackson, L. A. Jackson, A. S. Monto, E. T. Martin, E. A. Belongia, H. Q. McLean, M. Gaglani, K. Murthy, R. K. Zimmerman, M. P. Nowalk, A. M. Fry and B. Flannery (2018). “Influenza vaccine effectiveness among patients with high-risk medical conditions in the United States, 2012-2016.” Vaccine 36(52): 8047-8053.

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BACKGROUND: Annual influenza vaccination has been recommended for persons with high-risk conditions since the 1960s. However, few estimates of influenza vaccine effectiveness (VE) for persons with high-risk conditions are available. METHODS: Data from the U.S. Influenza Vaccine Effectiveness Network from 2012 to 2016 were analyzed to compare VE of standard-dose inactivated vaccines against medically-attended influenza among patients aged >/=6months with and without high-risk medical conditions. Patients with acute respiratory illness were tested for influenza by RT-PCR. Presence of high-risk conditions and vaccination status were obtained from medical records. VE by influenza virus type/subtype and age group was calculated for patients with and without high-risk conditions using the test-negative design. Interaction terms were used to test for differences in VE by high-risk conditions. RESULTS: Overall, 9643 (38%) of 25,369 patients enrolled during four influenza seasons had high-risk conditions; 2213 (23%) tested positive for influenza infection. For all ages, VE against any influenza was lower among patients with high-risk conditions (41%, 95% CI: 35-47%) than those without (48%, 95% CI: 43-52%; P-for-interaction=0.02). For children aged <18years, VE against any influenza was 51% (95% CI: 39-61%) and 52% (95% CI: 39-61%) among those with and without high-risk conditions, respectively (P-for-interaction=0.54). For adults aged >/=18years, VE against any influenza was 38% (95% CI: 30-45%) and 44% (95% CI: 38-50%) among those with and without high-risk conditions, respectively (P-for-interaction=0.21). For both children aged <18 and adults aged >/=18years, VEs against illness related to influenza A(H3N2), A(H1N1)pdm09, and influenza B virus infection were similar among those with and without high-risk conditions. CONCLUSIONS: Influenza vaccination provided protection against medically-attended influenza among patients with high-risk conditions, at levels approaching those observed among patients without high-risk conditions. Results from our analysis support recommendations of annual vaccination for patients with high-risk conditions.

Shang, M., J. R. Chung, M. L. Jackson, L. A. Jackson, A. S. Monto, E. T. Martin, E. A. Belongia, H. Q. McLean, M. Gaglani, K. Murthy, R. K. Zimmerman, M. P. Nowalk, A. M. Fry and B. Flannery (2018). “Influenza vaccine effectiveness among patients with high-risk medical conditions in the United States, 2012-2016.” Vaccine 36(52): 8047-8053.

Full text of this article.

BACKGROUND: Annual influenza vaccination has been recommended for persons with high-risk conditions since the 1960s. However, few estimates of influenza vaccine effectiveness (VE) for persons with high-risk conditions are available. METHODS: Data from the U.S. Influenza Vaccine Effectiveness Network from 2012 to 2016 were analyzed to compare VE of standard-dose inactivated vaccines against medically-attended influenza among patients aged >/=6months with and without high-risk medical conditions. Patients with acute respiratory illness were tested for influenza by RT-PCR. Presence of high-risk conditions and vaccination status were obtained from medical records. VE by influenza virus type/subtype and age group was calculated for patients with and without high-risk conditions using the test-negative design. Interaction terms were used to test for differences in VE by high-risk conditions. RESULTS: Overall, 9643 (38%) of 25,369 patients enrolled during four influenza seasons had high-risk conditions; 2213 (23%) tested positive for influenza infection. For all ages, VE against any influenza was lower among patients with high-risk conditions (41%, 95% CI: 35-47%) than those without (48%, 95% CI: 43-52%; P-for-interaction=0.02). For children aged <18years, VE against any influenza was 51% (95% CI: 39-61%) and 52% (95% CI: 39-61%) among those with and without high-risk conditions, respectively (P-for-interaction=0.54). For adults aged >/=18years, VE against any influenza was 38% (95% CI: 30-45%) and 44% (95% CI: 38-50%) among those with and without high-risk conditions, respectively (P-for-interaction=0.21). For both children aged <18 and adults aged >/=18years, VEs against illness related to influenza A(H3N2), A(H1N1)pdm09, and influenza B virus infection were similar among those with and without high-risk conditions. CONCLUSIONS: Influenza vaccination provided protection against medically-attended influenza among patients with high-risk conditions, at levels approaching those observed among patients without high-risk conditions. Results from our analysis support recommendations of annual vaccination for patients with high-risk conditions.

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.

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.

Ford, E. S., A. S. Magaret, C. W. Spak, S. Selke, S. Kuntz, L. Corey and A. Wald (2018). “Increase in HSV shedding at initiation of antiretroviral therapy and decrease in shedding over time on antiretroviral therapy in HIV and HSV-2 infected persons.” Aids 32(17): 2525-2531.

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OBJECTIVES: HIV-infected persons with chronic herpesvirus infections may experience paradoxical worsening after initiation of antiretroviral therapy (ART), but the impact of longer term ART is unclear. We evaluated the relationships between genital herpes simplex virus (HSV) shedding and ART initiation and time on therapy in HIV and HSV-2-infected persons. DESIGN: Prospective observational study. METHODS: Rates of HSV shedding in 45 HIV and HSV-2-infected persons on or off ART were prospectively followed over up to three, noncontiguous, 60-day periods, during which participants performed daily genital swabs for HSV detection by real-time HSV DNA PCR and reported symptoms. Initiation or discontinuation of ART was at the discretion of participants’ healthcare providers. RESULTS: In all, 6425 daily genital swabs were obtained from 45 persons (38 men and seven women) during 105 swabbing sessions. During the three sessions, 67, 74, and 92% of persons were on ART. HSV was detected on 26.5% of days in men and 22.3% of days in women. The overall rates of genital HSV shedding were 19.4% of days in persons not on ART, 30.2% in persons within 90 days of ART initiation, and 23.3% in persons on ART for longer than 90 days. After initiation of ART, HSV shedding decreased by 2% per month, or 23% per year (RR 0.98/month on ART; P = 0.0003 in adjusted analysis). This finding was consistent after including consideration of HIV viral load and CD4 cell count. CONCLUSIONS: HSV shedding increased significantly shortly after ART initiation, but decreased with time on prolonged ART.