Ken reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and provided and managed pharmacy care and drug information services. He regularly contributes to Contagion Live, HCP Live, Neurology Live, and Pain Medicine News.

Kenneth Bender, PharmD, MA

Four months of treatment with a rifapentine-moxifloxacin based anti-tuberculosis regimen produced the same survival rate with absence of

at 12 months as the conventional half-year regimen with rifampin-based treatment, in a phase 3 

 evaluating rifapentine based regimens with and without the fluoroquinolone in over 2000 patients in 34 sites around the world.

Susan Dorman, MD, the Medical University of South Carolina, Charleston, and colleagues of the AIDS Clinical Trials Group and the Tuberculosis Trials Consortium conducted the trial comparing 2 rifapentine-based experimental regimens against conventional treatment in patients newly diagnosed with 

 not resistant to isoniazid, rifampin, or fluoroquinolones.

The participants were randomly assigned in equal numbers to receive either a conventional regimen consisting of rifampin, isoniazid, pyrazinamide and ethambutol; or with rifampin replaced with either rifapentine or with rifapentine and moxifloxacin.

The investigators chose rifapentine, a cyclopentyl derivative of rifampin, as an alternative to rifampin following preclinical models that suggest that increasing exposure to rifamycins could shorten the time course for treating tuberculosis.

, and its longer half-life makes the drug an attractive option for increasing the duration of exposure to rifamycins while maintaining the once-daily dosing schedule that facilitates the completion of treatment," Dorman and colleagues explained.

The investigators also noted evidence that moxifloxacin exerts activity against 

, and that its addition to anti-tuberculosis regimens has accelerated sputum-culture conversion to negative status, albeit without yet shortening the requirement for 6 months of treatment.

Rifapentine was administered at a daily dose of 1200mg and moxifloxacin 400mg daily; with other drugs administered at standard doses adjusted for body weight. The medications in each regimen were administered 7 days per week, with the study protocol specifying direct observation of medications being taken at least 5 days per week. As food affects the absorption of rifapentine and rifampin differently, rifapentine was administered within 1 hour after ingesting food, while rifampin was taken on an empty stomach.

Dorman and colleagues reported that 4 months of treatment with the rifapentine with moxifloxacin based regimen (but not without moxifloxacin) was noninferior (within margin of 6.6 percentage points) to 6 months of the conventional rifampin-based treatment.In the microbiologically eligible populations, 15.5% of those on the rifapentine with moxifloxacin based regimen had an unfavorable outcome, compared to 14.6% on the longer rifampin-based regimen. Adverse events of grade 3 or higher occurred in 18.8% of the riapentine with moxifloxacin group, and 19.3% of those receiving the rifampin-based treatment.

The results were welcomed in an accompanying editorial,

"Shortening the Short Course of Tuberculosis Treatment"

, by Valerie Mizrahi, PhD, Institute of Infectious Diseases and Molecular Medicine and the Department of Pathology, Wellcome Center for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa, and Editor in Chief of 

Eric Rubin, MD, PhD, an infectious disease specialist.

"It was almost as though 6 months represented some strict limit—that is, until now," Mizrahi and Rubin enthused.

That this development has been long awaited is reflected in the years since Mizrahi's previous editorial in the 

"Shortening Treatment for Tuberculosis—Back to Basics,"

 in which she reviewed failure of 3 separate trials to achieve this outcome, and called for a closer look at the characteristics and potential susceptibility of 

Although they welcome the prospect of a shortened course of treatment, Mizrahi and Rubin offer some concerns about this regimen, including the need to take rifapentine after meals to maximize absorption. They also suggest that the conventional rifampin-based regimen has an advantage of comprising drugs that are not generally used for other infections.In addition to necessitating rapid drug-susceptibility testing for moxifloxacin, they note, the widespread use of the antibiotic for tuberculosis could promote resistance to fluoroquinolones in other bacteria.

"This trial does, however, establish an important principle: there is no magic 6 months of therapy," Mizrahi and Rubin declare.

"This trial not only proves that we can have a shorter short-course treatment, but also suggests that an even shorter short-course treatment might one day be feasible," they conclude.

Articles

Rifapentine-moxifloxacin based anti-tuberculosis regimen shortened the conventional six-month course of treatment to four.

New Anti-Tuberculosis Regimen Cures 2 Months Earlier

A newly validated decision-support product developed with machine learning predicted bacterial sepsis in immunocompromised recipients of allogenic hematopoietic cell transplant (allo-HCT) more reliably and with better prognostic performance than commonly used sepsis detection tools, despite atypical presentations of sepsis in this population.

“…sepsis is challenging to diagnose among recipients of allo-HCT,” indicated Margaret Lind, MPH, Department of Epidemiology, University of Washington, Seattle, WA, and colleagues.

“In individuals who are immunosuppressed, sepsis has less common presentations, manifests with subtle clinical findings, and progresses more rapidly than in immunocompetent populations,” Lind and colleagues explained.

With early and accurate detection of sepsis critical to improving outcomes, and with the possibility of reducing the early empirical broad-spectrum antibiotic use that is associated with increased antibiotic resistance and hospital-acquired infections, the investigators sought to develop decision tools that might perform better in this population than the National Early Warning Score (NEWS), the quick Sequential Organ Failure Assessment (qSOFA), or the Systemic Inflammatory Response Syndrome (SIRS).

Lind and colleagues describe using state-of-the-art stacked ensembling technique to develop two automated bacterial sepsis decision tools for recipients of allo-HCT with potential bloodstream infections (PBI): the Super HCT Bacterial Sepsis Learner (SHBSL) and the Clinical Factor-Specific Super HCT Bacterial Sepsis Learner (C-SHBSL).Both, they indicate, have the potential to be integrated into electronic medical record systems to provide patient-specific sepsis risk probability estimates, and to flag patients who are at high risk at the time of blood culture collection.

 of 1594 individuals who experienced at least 1 PBI, from among 1943 individuals who received their first allo-HCT at a designated treatment center in Seattle between June 2010 and June 2019.Of a total of 8131 observed PBIs, 238 (2.9%) were high-sepsis risk bacteremia.

Medical records for the first 100 days following the procedure or until an earlier death were retrospectively evaluated to compare predictive tools. The investigators note that this was a period of close patient monitoring by inpatient and outpatient transplant teams. Blood cultures were recommended for patients with fevers, and surveillance cultures were recommended weekly or biweekly for patients receiving high-dose glucocorticoids. Levofloxacin was used as the primary antibiotic prophylaxis during neutropenic periods; and patients with neutropenic fever received empirical therapy with ceftazidime, cefepime, or meropenem.

The predictive, decision-support tools were compared in relative area under the receiver operating characteristic curve (AUROC) for estimated vs observed outcomes.The investigators reported that the SHBSL had higher estimated discrimination and calibration for high-sepsis risk bacteremia and short-term mortality among the recipients of allo-HCT with PBIs.

Compared with high-sepsis risk bacteremia, the SHBSL had the highest AUC (0.85; 95% CI, 0.81-0.89) followed by the C-SHBSL (0.72; 95%CI, 0.66-0.78). SIRS had the highest AUC of the three previously available tools (0.64; 95%CI, 0.57-0.71).The SHBSL also had the highest AUCs for PBIs identified in inpatient (0.82; 95%CI, 0.76-0.89) and outpatient (0.82; 95% CI, 0.75-0.89) settings; as well as for 10-day and 28-day mortality.

"Unlike most automated sepsis estimation tools, which were built to improve early detection of clinically identified sepsis through real-time estimation, we built SBHSL and C-SHBSL to improve the accuracy of the sepsis risk estimation itself," Lind and colleagues declared.

"This decision was driven by the atypical presentation of sepsis within our study population, the desire to build tools functional in both inpatient and outpatient settings, the limited accuracy of existing clinical scores, and reliance on outcomes that require cultures," the investigators explained.

Machine learning improves prediction of bacterial sepsis among immunocompromised recipients of stem cell transplant.

Machine Learning Improves Prediction of Sepsis after Stem Cell Transplant

One year after the NIH announced formation of a public-private partnership to develop treatments for COVID-19, the 6th major research component will commence, with clinical trials to test repurposing of several candidate drugs to treat mild-to-moderate disease and avoid hospitalization.

SInce the NIH announced formation of ACTIV, Accelerating COVID-19 Therapeutic Interventions and Vaccines, in April 2020, the initiative has undertaken 5 major testing and development programs on, respectively: immune modulators; outpatient monoclonal antibodies and other therapies; inpatient monoclonal antibodies and other therapies; antithrombotics; and "big effect" trials, identifying phase 2 trials that evidence promise in late-stage clinical development.

ACTIV-6 protocol, for platform clinical trials of repurposing approved drugs for outpatients, the candidate agents that demonstrate efficacy in reducing symptoms of mild-to-moderate COVID-19 will be further evaluated for effects on clinical outcomes such as hospitalization and mortality, and long-term COVID-19 symptoms.

"While we're doing a good job with treating hospitalized patients with severe disease, we don't currently have an approved medication that can be self-administered to ease symptoms of people suffering from mild disease at home, and reduce the chance of their needing hospitalization," said NIH Director Francis Collins, MD, PhD, in the announcement."ACTIV-6 will evaluate whether certain drugs showing promise in small trials can pass the rigor of a larger trial."

The ACTIV-6 program, funded by the American Rescue Plan Act, will be overseen by the NIH's National Center for Advancing Translational Sciences (NCATS); with the Duke Clinical Research Institute (DCRI), Durham, North Carolina serving as clinical coordinating center and the Vanderbilt University Medical Center, Nashville, Tennessee serving as the trial data coordinating center.

, issued simultaneously with the NIH release,Susanna Naggie, MD, Vice Dean for Clinical Research, Duke University School of Medicine, and the principal investigator who will oversee the coordinating center, described the value of the platform trial, which will enable the concurrent study of up to 7 different drugs that will be selected from a pool of candidates.

"Even with the impressive progress that has been made on vaccines, the pandemic continues to evolve, with new variants and surges of infections in different regions of the world," Naggie stated."Therefore, there remains a critical need for ongoing clinical evidence generation about treatments for COVID-19 in order to meet public health needs, particularly treatments that can be easily administered by patients in their own home."

 from the NIH, enrollment in the ACTIV-6 platform trial of drugs to repurpose for COVID-19 is expected to open within a few weeks, for up to 13,500 participants who are at least 30 years old, and have tested positive for SARS-CoV-2 infection, and have experienced two or more mild-to-moderate symptoms of COVID-19 for no more than 7 days.

Researchers will assess changes in patients' symptoms over a 14-day period, as well as hospitalizations and deaths over a 28-day period.They will also assess long-term COVID-19 related symptoms at 90 days after treatment begins.Although the drugs to be tested have not been finalized, the announcement indicates that all will have established safety records, as well as early indications of potential effectiveness against COVID-19 from smaller or less controlled studies.

The ACTIV-6 platform trial will also focus on enrollment of people within minority, rural, or other communities that are significantly affected by COVID-19 but lack access to major academic medical centers that are the usual sites for large clinical trials.

The 6th major component of the 1-year old ACTIV public-private initiative of the NIH will test candidate drugs to repurpose for COVID-19.

NIH Announces New Research on Repurposing Drugs to Treat COVID-19

The rare blood clots that have been reported in 

 with the AstraZeneca SARS-CoV-2 vaccine, in vaccine-induced immune thrombotic thrombocytopenia (VITT), and in the 

 with the Johnson and Johnson (Janssen) vaccine, as cases of cerebral venous sinus thrombosis (CVST), pose a danger beyond the severe condition that appears to affect, by various estimates, from 4-6 persons per million to 1 in 40,000; and besides the interruption in distributing those vaccines, expected to be a temporary "pause" in the US, or permanently, as recently announced in 

The additional consequence of this serious but rare adverse effect could be a heightening of vaccine hesitancy and reduced acceptance of the protection afforded by vaccination.This could be mitigated, along with the danger to the rare individual, by research that has already begun to determine the pathogenic processes and identify those at particular risk—who might then be provided with alternative products.

 characterizing the episodes in Europe, which found similarity to thrombotic features of heparin-induced thrombocytopenia, is being followed by a number of investigations by the manufacturer as well as by academic consortia, according to a report in 

Among the questions that will be addressed by the research is whether the already-small risk could be reduced further with a smaller dose of the vaccine.

An Increasing vaccine hesitancy could also be addressed in ongoing public health education, which not only conveys the characteristics of the event, susceptible individuals and warning signs, but is informed by research into the factors and demographics that contribute to vaccine hesitancy.

Robert Kaplan, PhD and Arnold Milstein, MD, MPH, Clinical Excellence Research Center, Stanford University School of Medicine conducted a 

 in August and repeated it in December, of how the effectiveness and safety of a vaccine would Influence its acceptance.

Kaplan and Milstein note that while a safe and effective vaccine for SARS-CoV-2 virus has high potential to mitigate a severely damaging COVID-19 pandemic, refusal to accept the vaccine substantially diminishes the population impact.In their own national survey, conducted before the present study, they found that only one-third of respondents indicated that they would likely accept the vaccine, while approximately 1 in 5reported being very unlikely to take the vaccine under any circumstances.

"These findings suggest that, without a better understanding of the reasons for vaccine refusal, achieving herd immunity will be difficult," they observed.

To ascertain the influence of efficacy and safety of the vaccine on the likelihood of accepting vaccination, the investigators conducted a conjoint analysis of these factors in a sample of 1000 individuals across all 50 states, from the YouGov proprietary opt-in survey panel. They explain that the conjoint analysis is widely used in marketing to assess consumer preferences and predict consumer purchasing behavior, by presenting sets of option with various attributes—such as high risk, low benefit vs low risk high benefit medicines.

In the present study of vaccine acceptance, they posed the variables of benefits (50%, 75%, 90% effective), minor side effects (50%, 75%, and 90% probability of experiencing sore arm, headache or 1 day of low fever) and serious adverse reactions (incidence of 1/100,000 vaccinated, 1 per million, or 1 per 100 million).

Kaplan and Milstein report similar results from their August and December surveys.The probability of a high rate of effectiveness was the largest determinant of acceptance, regardless of potential side effects. Minor side effects of any probability did not influence acceptance. The chance of a serious adverse event, such as the provided example of permanent paralysis, had a small but significant effect; with the rate of 1/100,000 more likely to discourage use than the rarer occurrences of 1 in 1 or 100 million.There was no statistically significant interaction between the factors.

"The absence of interaction effects suggest that respondents consider the side effects and benefits independently," Kaplan and Milstein conclude.

In what might be a useful consideration in the current public health outreach to explain a serious but rare adverse effect of a vaccine, Kaplan and Milstein point out, "expected benefit was more influential in respondents' decision making than expected side effects."

Severe blood clots reported with 2 COVID-19 vaccines are rare, but possible heightening of vaccine hesitancy would lower floodgates to pandemic waves