Day: 03/09/2022

Childhood Tuberculosis — Time for Shorter and Differentiated Treatment

Posted by

0


Well before the Covid-19 pandemic disrupted tuberculosis care,1 long treatment duration has been a weak link in the continuum of care. But the past decade has been a turning point in the pioneering of shorter treatment and differentiated care, as opposed to the traditional, one-size-fits-all approach. Shortening of treatment is being achieved by exploiting longer-acting drugs, adding new drugs, or, for persons with nonsevere disease, targeting shorter regimens.2

For latent Mycobacterium tuberculosis infection, several shorter alternatives to the traditional 6 to 9 months of isoniazid therapy now exist, including a 3-month regimen of weekly rifapentine plus isoniazid or a 4-month regimen of daily rifampin.3 For drug-resistant tuberculosis, 6 months of oral-only regimens such as bedaquiline, pretomanid, and linezolid4 or these drugs plus moxifloxacin5 could replace the 24-month standard regimen. For drug-sensitive tuberculosis in adults, a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in a recent trial.6

Where does this leave children, a vulnerable group that is often excluded from randomized trials of new treatments? According to the World Health Organization, 1.1 million children worldwide became ill with tuberculosis in 2020, predominantly in low- and middle-income countries.7 Increasingly, childhood tuberculosis is also identified in the context of acute lower respiratory tract infection or pneumonia.8 However, difficulties in confirming a diagnosis of tuberculosis (particularly a lack of microbiologic confirmation), a long duration of treatment, lack of easy access to fixed-dose palatable pediatric formulations, pill burden, and medication side effects are big challenges in treating children. It is therefore timely and commendable that Turkova et al. present in this issue of the Journal9 the results of the SHINE trial — a trial that included only children and showed that 4 months of treatment provided similar efficacy to a standard 6-month regimen for nonsevere tuberculosis.

This multicenter, open-label trial involved 1204 children with symptomatic, nonsevere (as assessed radiologically), smear-negative tuberculosis. The median age of the participants was 3.5 years, and 11% of them had human immunodeficiency virus (HIV) infection. In children with microbiologic confirmation of tuberculosis (14% of the trial population), only those with drug-susceptible cases were included. Participants were randomly assigned in a 1:1 ratio to receive either 4 months (16 weeks) or 6 months (24 weeks) of antituberculosis therapy. All the participants received 8 weeks of standard treatment with isoniazid, rifampin, and pyrazinamide as a fixed-dose formulation, with or without ethambutol; this treatment was followed by either 8 weeks or 16 weeks of isoniazid and rifampin in a fixed-dose combination. The primary outcome was unfavorable status (defined as treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks.

In the primary analysis, the 4-month regimen was found to be noninferior to the standard 6-month regimen. Findings in all the subgroup analyses, including those stratified according to age, HIV infection status, sex, geographic region, body weight, use of ethambutol, or positivity on microbiologic testing, were similar to those in the primary analysis. Results of the safety analyses were similar in the two treatment groups, with adverse events occurring in approximately 8% of the participants in each group, with most events occurring during the first 8 weeks of treatment (during which the treatments were identical in the two groups). Adherence was high in each group, with 94% adherence to at least 80% of the doses throughout the assigned treatment duration. Retention in this trial was impressive, with 95% of the expected participants attending the 72-week visit. Besides the benefits of adherence and reduction in pill burden over time, a cost-effectiveness analysis indicated lower health care costs with the shorter regimen.

The next steps for implementation of the regimen used in the SHINE trial would include revision of global guidelines, adoption by countries, and scaling up of better diagnostic tools as well as pediatric fixed-dose formulations. Although the findings of this trial are applicable only to nonsevere tuberculosis, most cases of tuberculosis in children initially manifest as nonsevere disease, with low bacillary burden on smears and molecular tests.10 Thus, the trial findings will be applicable to most children with tuberculosis and can be adopted by national programs with the use of fixed-drug formulations that are already available.

However, a key barrier to implementation would be the identification of children with nonsevere tuberculosis. The use of microscopy to rule out smear-positive cases is probably unnecessary, given the low sensitivity in children and the replacement of microscopy with molecular tests such as Xpert MTB/RIF Ultra.10 Low, very low, or trace positive values on Xpert testing are most common in children with microbiologically confirmed tuberculosis10 and could be used as a proxy for smear-negative tuberculosis and to simultaneously rule out rifampin resistance. It is therefore imperative that countries invest more in microbiologic diagnosis with molecular testing for childhood tuberculosis, building on the laboratory capacity developed for Covid-19.1

Reliance on radiography of the chest to identify nonsevere disease may be a challenge in areas where radiology facilities are limited; interobserver variability in interpretation is also an issue. However, these concerns may be addressed with newer, ultra-portable digital radiography systems and artificial intelligence–based software for reading radiographs, with the latter requiring validation in children.11 Given the wide usefulness of radiographs beyond tuberculosis care, greater efforts are needed to make digital radiography more affordable and accessible, as an essential diagnostic tool in primary health care.

Source: NEJM

CT or Invasive Coronary Angiography in Stable Chest Pain

Posted by

0


Abstract

BACKGROUND

In the diagnosis of obstructive coronary artery disease (CAD), computed tomography (CT) is an accurate, noninvasive alternative to invasive coronary angiography (ICA). However, the comparative effectiveness of CT and ICA in the management of CAD to reduce the frequency of major adverse cardiovascular events is uncertain.

METHODS

We conducted a pragmatic, randomized trial comparing CT with ICA as initial diagnostic imaging strategies for guiding the treatment of patients with stable chest pain who had an intermediate pretest probability of obstructive CAD and were referred for ICA at one of 26 European centers. The primary outcome was major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) over 3.5 years. Key secondary outcomes were procedure-related complications and angina pectoris.

RESULTS

Among 3561 patients (56.2% of whom were women), follow-up was complete for 3523 (98.9%). Major adverse cardiovascular events occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 (3.0%) in the ICA group (hazard ratio, 0.70; 95% confidence interval [CI], 0.46 to 1.07; P=0.10). Major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13 to 0.55). Angina during the final 4 weeks of follow-up was reported in 8.8% of the patients in the CT group and in 7.5% of those in the ICA group (odds ratio, 1.17; 95% CI, 0.92 to 1.48).

CONCLUSIONS

Among patients referred for ICA because of stable chest pain and intermediate pretest probability of CAD, the risk of major adverse cardiovascular events was similar in the CT group and the ICA group. The frequency of major procedure-related complications was lower with an initial CT strategy.

Source: NEJM

Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer

Posted by

0


Abstract

BACKGROUND

In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.

METHODS

Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan–Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.

RESULTS

After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval [CI], 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P=0.008). No new safety signals were observed.

CONCLUSIONS

First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. 

Source: NEJM

Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina

Posted by

0


Abstract
BACKGROUND
The duration of protection afforded by coronavirus disease 2019 (Covid-19) vaccines in the United States is unclear. Whether the increase in postvaccination infections during the summer of 2021 was caused by declining immunity over time, the emergence of the B.1.617.2 (delta) variant, or both is unknown.

METHODS
We extracted data regarding Covid-19–related vaccination and outcomes during a 9-month period (December 11, 2020, to September 8, 2021) for approximately 10.6 million North Carolina residents by linking data from the North Carolina Covid-19 Surveillance System and the Covid-19 Vaccine Management System. We used a Cox regression model to estimate the effectiveness of the BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson–Janssen) vaccines in reducing the current risks of Covid-19, hospitalization, and death, as a function of time elapsed since vaccination.

RESULTS
For the two-dose regimens of messenger RNA (mRNA) vaccines BNT162b2 (30 μg per dose) and mRNA-1273 (100 μg per dose), vaccine effectiveness against Covid-19 was 94.5% (95% confidence interval [CI], 94.1 to 94.9) and 95.9% (95% CI, 95.5 to 96.2), respectively, at 2 months after the first dose and decreased to 66.6% (95% CI, 65.2 to 67.8) and 80.3% (95% CI, 79.3 to 81.2), respectively, at 7 months. Among early recipients of BNT162b2 and mRNA-1273, effectiveness decreased by approximately 15 and 10 percentage points, respectively, from mid-June to mid-July, when the delta variant became dominant. For the one-dose regimen of Ad26.COV2.S (5×1010 viral particles), effectiveness against Covid-19 was 74.8% (95% CI, 72.5 to 76.9) at 1 month and decreased to 59.4% (95% CI, 57.2 to 61.5) at 5 months. All three vaccines maintained better effectiveness in preventing hospitalization and death than in preventing infection over time, although the two mRNA vaccines provided higher levels of protection than Ad26.COV2.S.

CONCLUSIONS
All three Covid-19 vaccines had durable effectiveness in reducing the risks of hospitalization and death. Waning protection against infection over time was due to both declining immunity and the emergence of the delta variant.

Discussion

The estimates of vaccine effectiveness from this study are consistent with and complement the estimates of vaccine efficacy from phase 3 trials.1-3,18,19 Specifically, the estimated peak levels for the three vaccines in this study are similar to those in phase 3 trials, although phase 3 trials were not powered to determine when the peak occurs. The large sample size of this study allowed us to pinpoint the timing of the peak. The estimates of long-term vaccine effectiveness against Covid-19 shown in this study are lower than results based on limited phase 3 trial data18,19; however, our study included both symptomatic and asymptomatic infections, and vaccine effectiveness against asymptomatic infection is expected to be lower than that against symptomatic infection, which was the primary end point in the phase 3 trials.

Our results showed that the effectiveness of the two messenger RNA (mRNA) vaccines — BNT162b2 and mRNA-1273 — was very high and durable against hospitalization and death and that mRNA-1273 was somewhat more effective than BNT162b2 against Covid-19. Note that BNT162b2 was given at a lower dose than mRNA-1273 (30 μg per injection vs. 100 μg per injection). In addition, Ad26.COV2.S offered a high level of protection against hospitalization and death, and its effectiveness against Covid-19 reached a peak level similar to that of the two mRNA vaccines 1 month after vaccination and then started to decline.

A recent study from Israel showed that the rate of Covid-19 during the period of July 11 to 31, 2021, among persons who had become fully vaccinated with BNT162b2 in January was 1.6 times as high as the rate among persons who had become fully vaccinated with BNT162b2 in March, and the rate ratio for severe disease was more than 1.8.11 These differences seem more substantial than those observed in the main analysis of our study; however, when a vaccine is highly effective, comparison of the event rates between persons vaccinated in two different time periods conveys a greater sense of waning than comparison of the vaccine effectiveness. Indeed, in our study, the rate of Covid-19 during the period of July 11 to 31, 2021, among persons who had received the second dose of BNT162b2 in January was 1.5 times as high as the rate among persons who had received the second dose of BNT162b2 in March; the rate ratio for hospitalization could not be calculated because of small numbers and incomplete data. A recent study from the state of New York compared vaccine effectiveness in May, June, July, and August of 2021 among persons who were vaccinated in January–February, March, and April of 2021.12 The life-table method was used to estimate hazard rates over 7-day intervals. The resulting estimates of vaccine effectiveness are unstable, and the confidence intervals are too wide to lead to firm conclusions.

Our study was observational and thus was limited by confounding bias. We adjusted for measured confounders (age, sex, race or ethnic group, geographic region, and county-level vaccination rate). Of greater importance, we measured the time to disease occurrence from the start of the study in order to compare disease incidence between vaccinated and unvaccinated persons on the same date, thus avoiding confounding due to time trends (e.g., level of community transmission and prevalence of new variants). However, persons who choose not to be vaccinated may differ from those who choose to be vaccinated in terms of their use of other prevention measures. In addition, persons who have Covid-19 symptoms may delay vaccination. It would be difficult to quantify the potential bias caused by these confounding factors.

This study included data regarding vaccination history only for persons who were vaccinated in North Carolina by a North Carolina state provider or federal pharmacy provider. Recipient-level vaccination data for North Carolina residents who were vaccinated outside North Carolina and for residents who were vaccinated through a federal entity (Department of Defense, Veterans Health Administration, Indian Health Service, or Federal Bureau of Prisons) are not available through CVMS and therefore were not included in the analysis. Those data represent less than 5% of total vaccine administrations in North Carolina.

Routinely linked communicable-disease and vaccine-registry data from comprehensive statewide surveillance systems are useful for studying vaccine effectiveness. The methods developed for this study can be applied to surveillance-linked laboratory and vaccination data from other states. By combining data from multiple states, we would be able to gain a more comprehensive understanding of vaccine effectiveness in the United States. With additional follow-up data, we would be able to evaluate not only the effectiveness of the original vaccine series beyond 9 months but also the effectiveness of the booster programs and the need for additional boosters.

Source: NEJM

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer

Posted by

0


Abstract

BACKGROUND

In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits.

METHODS

In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization.

RESULTS

Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of −0.3 percentage points (two-sided 90% CI, −2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported.

CONCLUSIONS

In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years.

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children

Posted by

0


Abstract

BACKGROUND

Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.

METHODS

We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.

RESULTS

From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, −0.4 percentage points; 95% confidence interval, −2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).

CONCLUSIONS

Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542. opens in new tab.)

Discussion

The SHINE trial evaluated the duration of antituberculosis treatment in children with nonsevere, drug-susceptible tuberculosis who were living in countries with a high burden of tuberculosis, where nearly 90% of cases of tuberculosis in children occur.19 The trial showed the noninferiority of 4 months as compared with the standard 6 months of treatment, with the upper boundary of the 95% confidence interval being below the prespecified margin of 6 percentage points. Consistency of results across all the analyses, including a key secondary analysis in a subgroup of children who were adjudicated to have tuberculosis at baseline, was observed. Participants had a good response to treatment with few adverse drug reactions, most of which occurred before 4 months, during the period when the two trial groups had the same treatment regimen.

Shortening treatment for drug-susceptible tuberculosis is a key goal for both adults and children. Early trials showed that it was possible to shorten the treatment duration in adults with culture-negative disease.20-22 A meta-analysis of treatment-duration trials involving adults showed that 4-month drug regimens were efficacious in adults with paucibacillary tuberculosis who had disease with a sputum-smear grade of less than 2+ (<1 acid-fast bacillus per field) or noncavity disease.23 Recently, the Tuberculosis Trials Consortium Study 31/AIDS Clinical Trials Group A5349 trial showed the noninferiority of a 4-month rifapentine-based regimen containing moxifloxacin, as compared with the 6-month standard regimen, for all forms of drug-susceptible tuberculosis (including cavity disease) in adults and adolescents.24 Challenges remain in terms of the availability of child-friendly formulations of rifapentine and moxifloxacin, data on doses in children, and cost. However, our results show that a new regimen with new drugs is not necessary for the shortening of treatment in the majority of children with drug-susceptible tuberculosis, since such treatment shortening can be accomplished with the affordable, child-friendly, fixed-dose combinations that are already available.25

This trial showed the feasibility of identifying children with nonsevere disease. We used a pragmatic approach by following routine screening procedures and reviewing chest radiographs to assess the severity of respiratory tuberculosis. Despite perceived difficulties of obtaining respiratory samples in children, such challenges were overcome with appropriate training, and samples were successfully obtained for tuberculosis testing in all 1204 children who underwent randomization. The trial included children with HIV infection as well as those without HIV infection, with consistent results.

Most children with tuberculosis have paucibacillary and nonsevere disease with low rates of microbiologic tuberculosis confirmation in routine care. To ensure the applicability of our results to clinical practice and the spectrum of disease that is most prevalent in children, we did not limit the trial to bacteriologically confirmed tuberculosis. We adapted the pediatric consensus algorithm for diagnosis of intrathoracic tuberculosis13 to both intrathoracic tuberculosis and peripheral lymph-node tuberculosis and used independent expert review and central reading of chest radiographs, with blinding to the treatment assignments, to ensure objective categorization of tuberculosis status. The end-point review committee, whose members were unaware of the randomized group assignments, reviewed tuberculosis outcomes to minimize the effect of treatment assignment on adjudication.

Our trial had several strengths. It was well-powered, and we observed 94% adherence (to the receipt of ≥80% of the doses) in the assigned groups and 95% retention of trial participants, findings that increase confidence in the results. We assumed in the sample-size calculation that 8% of the participants in the 6-month group would have an unfavorable status, and we observed this result in 7% of the participants overall in the trial. However, events in 3% of the participants occurred after month 4, when the trial groups were receiving different durations of the treatment, which we had not anticipated when we designed the trial.

The trial also has several limitations. One limitation is that this trial was open-label, which had the potential to result in more frequent treatment extensions in the 4-month group, contributing to more unfavorable outcomes in this group. Despite this possible disadvantage in the 4-month group, the results showed consistently that the 4-month regimen was as good as the 6-month regimen. Another limitation relates to the generalizability of our results to settings where chest radiographs are not available for characterizing nonsevere tuberculosis.

Our inclusion criteria for the trial required smear microscopy to be undertaken to rule out more severe forms of respiratory tuberculosis. With the current rollout of rapid molecular diagnostic tests replacing smear microscopy,26 this may pose a challenge to implementation on the basis of the trial results. However, smear-grade and Xpert semiquantitative results have been shown to be correlated.27 In our trial, most Xpert results from respiratory samples were negative and the few positive Xpert samples had low or very low semiquantitative results, which suggest that the trial findings can be extrapolated to settings where Xpert is replacing smear testing and that children with negative, low, or very low positive values on Xpert testing can be categorized as having nonsevere tuberculosis. It will be useful in future implementation studies to explore treatment shortening in all children who are treated for nonsevere, drug-susceptible tuberculosis, regardless of smear or Xpert results.

In this trial, we found that 4 months of antituberculosis treatment was noninferior to 6 months of therapy in children with drug-susceptible, nonsevere, smear-negative tuberculosis. The results suggest that a stratified medicine approach as an alternative to the one-size-fits-all strategy of treatment for presumptive drug-susceptible tuberculosis could be implemented in children with nonsevere tuberculosis.

Source: NEJM

Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2

Posted by

0


The omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (Covid-19), has spread rapidly around the world and has already become the predominant variant circulating in many countries. As of February 2022, omicron variants have been divided into four distinct sublineages: BA.1, BA.1.1, BA.2, and BA.3.1 Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant.2

As compared with the Wuhan/Hu-1/2019 reference strain, the sublineage BA.2 of the omicron variant has 16 amino acid substitutions in the receptor-binding domain of the spike (S) protein of SARS-CoV-2,2 which is the primary target for monoclonal antibody–based therapy. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages.

Accordingly, we examined the neutralizing ability of therapeutic monoclonal antibodies that have been approved by the Food and Drug Administration, individually and in combination, against the omicron BA.2 subvariant hCoV-19/Japan/UT-NCD1288-2N/2022 (omicron/BA.2; NCD1288), which was isolated from a traveler who arrived in Japan from India. Whole-genome sequencing analysis of the NCD1288 virus stock confirmed that it had the 16 substitutions that are characteristic of the omicron variant in the receptor-binding domain of the S protein, as compared with the Wuhan/Hu-1/2019 reference strain (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org).Table 1.Efficacy of Monoclonal Antibodies and Antiviral Drugs against the Omicron/BA.2 Subvariant in Vitro.

A live-virus focus reduction neutralization test (FRNT) showed that both LY-CoV016 (marketed as etesevimab) and LY-CoV555 (marketed as bamlanivimab), individually and in combination, lost neutralizing activity against omicron/BA.2 (NCD1288) (Table 1). These findings are similar to our previous findings with omicron/BA.1 (hCoV-19/Japan/NC928-2N/2021; NC928)3 and omicron/BA.1.1 (hCoV-19/Japan/NC929-1N/2021; NC929).4 BA.1.1, a subvariant of BA.1, has the R346K mutation in the S protein (Table S2). However, REGN10987 (marketed as imdevimab), which was previously shown to lose neutralizing activity against omicron/BA.1 (NC928) and omicron/BA.1.1 (NC929),3,4 had neutralizing activity against omicron/BA.2 (NCD1288).

In addition, the combination of REGN10987 and REGN10933 (marketed as casirivimab) also inhibited omicron/BA.2 but did not inhibit omicron/BA.1 or omicron/BA.1.1. However, the FRNT50 (the titer of monoclonal antibodies required for a 50% reduction in the number of infectious foci) value of this combination therapy was higher by a factor of 43.0 to 143.6 for omicron/BA.2 than for an ancestral strain — SARS-CoV-2/UT-NC002-1T/Human/2020/Tokyo (NC002) — and other variants of concern (i.e., the alpha [B.1.1.7], beta [B.1.351], gamma [P.1], and delta [B.1.617.2] variants).

REGN10933, COV2-2196 (marketed as tixagevimab), and COV2-2130 (marketed as cilgavimab) neutralized omicron/BA.2. The COV2-2196–COV2-2130 combination inhibited omicron/BA.2 with a low FRNT50 value (14.48 ng per milliliter); however, the FRNT50 values of this combination were higher by a factor of 1.4 to 8.1 for omicron/BA.2 than for the ancestral strain and other variants of concern.

S309 (the precursor of sotrovimab), which has been shown to have lower neutralizing activity against omicron/BA.1 and omicron/BA.1.1 than against the ancestral strain and other variants of concern,3,4 had even less neutralizing activity against omicron/BA.2 in our study. The FRNT50 value of this monoclonal antibody was higher by a factor of 12.2 to 49.7 for omicron/BA.2 than for the ancestral strain and other variants of concern.

The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern (i.e., 50% inhibitory concentration values for these three agents that differed by factors of 2.5 to 4.5, 0.7 to 1.6, and 1.5 to 3.3, respectively) (Table 1).3 Clinical studies are warranted to determine whether these antiviral therapies are indeed effective against omicron/BA.2 infections. Our data indicate that some therapeutic monoclonal antibodies (REGN10987–REGN10933, COV2-2196–COV2-2130, and S309) have lower neutralizing activity against omicron/BA.2 than against earlier variant strains.

Source: NEJM

Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use

Posted by

0


Sotrovimab is a monoclonal antibody that is available under emergency use authorization for the treatment of patients who are at risk for progression of coronavirus disease 2019 (Covid-19) to severe disease.1 Sotrovimab is thought to neutralize all sarbecoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by binding to a highly conserved epitope within the receptor-binding domain.2 However, the use of SARS-CoV-2–specific monoclonal antibodies to target a single viral epitope warrants caution because of the risk of rapid development of mutations that confer resistance after exposure to these antibodies.2-4 Mutations at positions S:E340K/A/V and S:P337L/T (Figure 1A) have been associated with a reduction by a factor of 100 to 297 in neutralization by sotrovimab.5

We reviewed the first 100 consecutive patients who received sotrovimab at health care facilities in the Western Sydney Local Health District in New South Wales, Australia, during the B.1.617.2 (delta) variant outbreak between August and November 2021 (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). We identified 8 patients (Patients R001 through R008) with reverse transcriptase–polymerase-chain-reaction (RT-PCR) assays that were persistently positive for SARS-CoV-2 and for whom respiratory tract specimens obtained before and after the use of sotrovimab were available.

Genomic analysis showed that 4 of these 8 patients (Patients R001 through R004) acquired previously defined receptor-binding domain mutations within 6 to 13 days after they received sotrovimab (Figure 1C and Table S1). Mutations in S:E340 developed in all 4 patients, findings that are concordant with those in the Covid-19 Monoclonal Antibody Efficacy Trial–Intent to Care Early (COMET-ICE).2 Cultures obtained from these patients remained positive for 23, 24, 12, and 15 days, respectively, after they received sotrovimab (Table S2). Read frequencies of S:E340K/A/V mutations increased over the course of infection; the proportion of the viral population carrying S:E340K/A/V exceeded 75% by day 7 in Patient R002, by day 13 in Patient R003, and by day 37 in Patient R004 (Figure 1C and Table S2). In addition, a minority variant developed in Patient R002 at position P337L after fixation of the S:E340K mutation. A retrospective review of 11,841 SARS-CoV-2 genomes in the Global Initiative on Sharing All Influenza Data database (a site for compiling sequence data on viruses) (Table S3) and reported in New South Wales, Australia, identified 4 additional patients with S:E340 mutations. In 1 patient, the SARS-CoV-2 genome was detected 5 days after sotrovimab treatment, and in another it was detected 11 days after treatment.

These data show the persistence of viable SARS-CoV-2 in patients after sotrovimab infusions and the rapid development of spike gene mutations associated with high-level sotrovimab resistance in vitro. These findings underscore the importance of stewardship of monoclonal antibodies, particularly because sotrovimab is one of the few monoclonal antibodies with retained activity against the B.1.1.529 (omicron) variant.1 Postmarketing genomic surveillance of patients who receive monoclonal antibodies for the treatment of SARS-CoV-2 infection is prudent in order to minimize the risk of both treatment failure and the transmission of potentially resistant SARS-CoV-2 variants in health care settings and the community, given that SARS-CoV-2 may be isolated up to 24 days after sotrovimab treatment.

Source: NEJM

Effect of mRNA Vaccine Boosters against SARS-CoV-2 Omicron Infection in Qatar

Posted by

0


Abstract

BACKGROUND

Waning of vaccine protection against coronavirus disease 2019 (Covid-19) and the emergence of the omicron (or B.1.1.529) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have led to expedited efforts to scale up booster vaccination. Protection conferred by booster doses of the BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna) vaccines in Qatar, as compared with protection conferred by the two-dose primary series, is unclear.

METHODS

We conducted two matched retrospective cohort studies to assess the effectiveness of booster vaccination, as compared with that of a two-dose primary series alone, against symptomatic SARS-CoV-2 infection and Covid-19–related hospitalization and death during a large wave of omicron infections from December 19, 2021, through January 26, 2022. The association of booster status with infection was estimated with the use of Cox proportional-hazards regression models.

RESULTS

In a population of 2,239,193 persons who had received at least two doses of BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine, those who had also received a booster were matched with persons who had not received a booster. Among the BNT162b2-vaccinated persons, the cumulative incidence of symptomatic omicron infection was 2.4% (95% confidence interval [CI], 2.3 to 2.5) in the booster cohort and 4.5% (95% CI, 4.3 to 4.6) in the nonbooster cohort after 35 days of follow-up. Booster effectiveness against symptomatic omicron infection, as compared with that of the primary series, was 49.4% (95% CI, 47.1 to 51.6). Booster effectiveness against Covid-19–related hospitalization and death due to omicron infection, as compared with the primary series, was 76.5% (95% CI, 55.9 to 87.5). BNT162b2 booster effectiveness against symptomatic infection with the delta (or B.1.617.2) variant, as compared with the primary series, was 86.1% (95% CI, 67.3 to 94.1). Among the mRNA-1273–vaccinated persons, the cumulative incidence of symptomatic omicron infection was 1.0% (95% CI, 0.9 to 1.2) in the booster cohort and 1.9% (95% CI, 1.8 to 2.1) in the nonbooster cohort after 35 days; booster effectiveness against symptomatic omicron infection, as compared with the primary series, was 47.3% (95% CI, 40.7 to 53.3). Few severe Covid-19 cases were noted in the mRNA-1273–vaccinated cohorts.

CONCLUSIONS

The messenger RNA (mRNA) boosters were highly effective against symptomatic delta infection, but they were less effective against symptomatic omicron infection. However, with both variants, mRNA boosters led to strong protection against Covid-19–related hospitalization and death. (Funded by Weill Cornell Medicine–Qatar and others.)

Discussion

BNT162b2 booster vaccination was associated with an 86.1% reduction in the incidence of symptomatic delta variant infection and a 49.4% reduction in the incidence of symptomatic omicron infection. With the mRNA-1273 booster, the reduction in the incidence of symptomatic infection with the omicron variant was similar at 47.3%. Fewer cases of severe Covid-19 were observed in the booster cohorts than in the nonbooster cohorts, which is consistent with the strong protection against hospitalization and death associated with the booster. Moreover, cases of severe Covid-19 were rare in both the booster and nonbooster cohorts despite the large number of infections. These findings affirm the durability of vaccine protection against hospitalization and death several months after receipt of the second dose.1,2

In the context of a global expansion of the omicron variant and the dwindling incidence of the delta variant, these findings may suggest that a longer-term strategy for a global response is the development and administration of a new generation of broadly effective vaccines rather than continuing with a strategy of repeated booster vaccination with existing vaccines. Pan-coronavirus vaccines35 would target a broad range of existing and future SARS-CoV-2 variants.

The effectiveness of the BNT162b2 booster, as compared with that of the two-dose primary series, was slightly higher than that of the mRNA-1273 booster. This may be explained by the higher baseline mRNA-1273 vaccine effectiveness and slower waning of effectiveness after the second dose.2,10,11 Possibly because of less waning, the effectiveness of both mRNA vaccines, as compared with that of the two-dose primary series, was lower in persons who had received the booster 8 months or less after the second dose than in those who had received it more than 8 months after the second dose.

The estimates of effectiveness of the BNT162b2 and mRNA-1273 vaccines against the delta and omicron variants are broadly consistent with the growing evidence of the effectiveness of mRNA vaccines against these variants in other countries.22-24,36-39 However, in our study, the effectiveness of boosters was compared with that of the two-dose primary series; we did not compare the outcomes among persons who received boosters with those among unvaccinated persons. Nevertheless, with the waning of vaccine protection against infection over time after the second dose1,2 — and more so against infection with the omicron variant36 — the effectiveness of boosters as compared with that of the primary series should be only slightly lower than the protection afforded by boosters as compared with no vaccination.

This study has limitations. With the durable effectiveness conferred by a two-dose primary series of BNT162b2 and mRNA-1273 vaccines against Covid-19–related hospitalization and death,1,2 the lower severity of omicron as compared with that of previous variants,40 the young population of Qatar,15 and the time lag between infection and severe forms of Covid-19, we had insufficient data to estimate the effectiveness of the mRNA-1273 vaccine booster against Covid-19–related hospitalization and death. In this observational study, the vaccinated cohorts were aware of which vaccines they received and the participants did not undergo randomization, so potentially unmeasured or uncontrolled confounding cannot be ruled out. Although the cohorts were matched for sex, 10-year age group, nationality, and calendar week of the second-dose vaccination, matching was not possible for other factors such as coexisting conditions, occupation, or geographic location because such data were not available to the investigators. With the large wave of omicron variant infections, the use of rapid antigen testing was expanded to supplement PCR testing beginning on January 5, 2022, but information on symptoms and the reasons for testing was not available to be included in the analysis.

Matching was performed to control for factors that are known to affect exposure to SARS-CoV-2 infection in Qatar.15 Matching according to 10-year age group may have partially reduced potential bias due to coexisting conditions. The number of persons with severe chronic conditions is also small in the young population of Qatar.15,19 In the first phase of the vaccine rollout, the national list of vaccine prioritization included only 19,800 persons (of all age groups) with serious coexisting conditions.1 Matching according to nationality may have partially controlled for the differences in occupational risk, given the statistical association between the nationality of workers and occupation type in Qatar.15,25-28 Qatar is essentially a city-state, and the incidence of SARS-CoV-2 infection was broadly distributed across the country’s neighborhoods and areas; thus, geographic location is not likely to have been a confounding factor. The use of rapid antigen testing may not have differentially affected the investigated cohorts because it was broadly implemented. A strength of this study is the exclusion of persons with a documented previous infection, because the presence of a previous infection may affect booster protection.10

In this study, mRNA boosters were highly effective against infection with the delta variant but were less effective against infection with the omicron variant. However, these boosters led to strong protection against Covid-19–related hospitalization and death due to both variants. Given future waves of SARS-CoV-2 infections that may be driven by new variants, these findings may suggest the need for the development of a new generation of vaccines that target a broad range of variants to confront virus evolution, rather than a continued strategy of repeated boosters with existing vaccines.

Source: NEJM

Exercise Blood Pressure in Heart Failure With Preserved and Reduced Ejection Fraction

Posted by

0


Abstract

Objectives

This study aimed to evaluate hemodynamic correlates of inducible blood pressure (BP) pulsatility with exercise in heart failure with preserved ejection fraction (HFpEF), to identify relationships to outcomes, and to compare this with heart failure with reduced ejection fraction (HFrEF).

Background

In HFpEF, determinants and consequences of exercise BP pulsatility are not well understood.

Methods

We measured exercise BP in 146 patients with HFpEF who underwent invasive cardiopulmonary exercise testing. Pulsatile BP was evaluated as proportionate pulse pressure (PrPP), the ratio of pulse pressure to systolic pressure. We measured pulmonary arterial catheter pressures, Fick cardiac output, respiratory gas exchange, and arterial stiffness. We correlated BP changes to central hemodynamics and cardiovascular outcome (nonelective cardiovascular hospitalization) and compared findings with 57 patients with HFrEF from the same referral population.

Results

In HFpEF, only age (standardized beta = 0.593; P < 0.001), exercise stroke volume (standardized beta = 0.349; P < 0.001), and baseline arterial stiffness (standardized beta = 0.182; P = 0.02) were significant predictors of peak exercise PrPP in multivariable analysis (R = 0.661). In HFpEF, lower PrPP was associated with lower risk of cardiovascular events, despite adjustment for confounders (HR:0.53 for PrPP below median; 95% CI: 0.28-0.98; P = 0.043). In HFrEF, lower exercise PrPP was not associated with arterial stiffness but was associated with lower peak exercise stroke volume (P = 0.013) and higher risk of adverse cardiovascular outcomes (P = 0.004).

Conclusions

In HFpEF, greater inducible BP pulsatility measured using exercise PrPP reflects greater arterial stiffness and higher risk of adverse cardiovascular outcomes, in contrast to HFrEF where inducible exercise BP pulsatility relates to stroke volume reserve and favorable outcome.

Source: JACC