Jared Kaltwasser

The interplay between type 1 interferons (IFN-I) and the HIV-1 virus is dynamic, according to new research, with IFN-I resistance highest at times of viral rebound.

, offers new insights into the role of IFN-I in HIV-1 infection, and could help pave the way for the 

 to effectively be used to help control, and possibly cure, the virus.

IFN-I are proinflammatory and immunomodulatory cytokines that have potent direct and indirect antiviral effects. However, investigators have yet to fully characterize how these interferons interact with the HIV-1 virus over time, a fact that has limited their potential use in HIV cure strategies.

Corresponding author Marcos VP Gondim, PhD, of the University of Pennsylvania, and colleagues, noted that up-regulation of IFN-I is one of the earliest innate responses to HIV-1 and its simian corollary, SIV, with high rates of the interferons detectable in the plasma prior to peak viremia. They said IFN-I, including 

 and IFNβ inferons, have been shown to help control HIV/SIV replication in CD4+ T cells and macrophages.

“Consistent with this, pretreatment of rhesus macaques with exogenous IFNα2 increased the number of intrarectal challenges required to achieve systemic SIVmac infection and vaginal administration of IFNβ protected rhesus macaques from recombinant SIV/HIV (SHIV) infection.”

The inverse also proved true–blocking IFN-I led to faster disease progression.

However, despite the benefits of IFN-I during acute infection, sustained IFN-I signalling in chronic infection appears to have a deleterious effect, correlating with higher viral load in untreated patients.

The dynamic nature of the effects of IFN-I has led to mixed results in studies aimed at evaluating the therapeutic possibilities of the interferons. Gondim and colleagues therefore sought to better understand the kinetics and magnitude of IFN-mediated pressures over time, and the degree to which such changes were uniform in individuals with different rates of disease progression.

The investigators used 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 people living with HIV, and then characterized the IFN-I sensitivity of the virus after transmission or after antiretroviral therapy (ART) and treatment interruption. They looked for IFNα2 and IFNβ concentrations to see which levels reduced viral replication, finding that the sensitivity of HIV-1 isolates to IFN-I inhibition consistently changed over time.

“Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease,” they wrote.

HIV-1 isolates obtained during ART therapy were relatively IFN-I sensitive, the investigators found, but viruses that rebounded after treatment interruption had the highest degree of resistance observed at any time.

“These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption,” Gondim and colleagues wrote.

The investigators said the finding that resistance is highest during viral rebound is an important factor to be considered when designing studies involving treatment interruption. They said the response will also be important as future studies attempt to use the interferons to cure the virus.

Articles

A study found patients with acute infection and those with viral rebound after antiretroviral therapy interruption had the highest viral resistance to type 1 interferons.

Interplay Between HIV-1, Type 1 Interferons is Dynamic Over Time

Moderna’s coronavirus disease 2019 (COVID-19) vaccine showed a 94.1% efficacy rate in its phase 3 trial, and serious adverse events were rare, occurring in just 0.6% of patients in both the vaccine and placebo groups.

The US Food and Drug Administration (FDA) gave emergency use authorization to the vaccine, named mRNA-1273, 

; the data used to support the approval were published Dec. 30 

, is an mRNA-based vaccine that encodes the perfusion stabilized full-length spike protein of the SARS-CoV-2 virus and is encapsulated in a lipid nanoparticle. It is administered in a 100 μg injection, with two doses given 28 days apart.

The study was designed to compare the risk of COVID-19 infection among those with and without the vaccine. Cases with symptom onset at least 14 days after the second injection in patients who had not previously been infected were considered to be new infections.

The study had an enrollment of 30420 patients, divided equally, with half receiving the vaccine and half receiving placebo. Of the total enrolled, 2.2% had evidence of SARS-CoV-2 infection at the start of the study, and 96% of patients received both injections.

Following administration of both injections, just 11 patients in the trial’s vaccine arm were confirmed to have symptomatic COVID-19, a rate of 3.3 per 1000 person-years. In the placebo group, 185 participants became infected with the virus, a rate of 56.5 per 1000 person-years.

Just 30 patients developed severe COVID-19, and only one patient died; all of the patients with severe disease were in the placebo group.

The vaccine was developed on a rapid timetable, with the study launching in July 2020. The cutoff for data collection was November 21, 2020.

While the efficacy data were impressive, much of the attention surrounding COVID-19 vaccine research has focused on safety data. Some fear the short development timetable and considerable public pressure for regulators to approve a vaccine could obscure potential safety risks.

However, the early data from the mRNA-1273 trial suggest significant adverse effects were very rare.

While injection-site solicited adverse events, mostly grades 1 and 2, occurred in more than 80% of patients in the vaccine group following both doses, those symptoms went away within 2 to 3 days. Delayed injection-site reactions occurred in just 0.8% of patients following the first dose and 0.2% of patients following the second dose, and those resolved within 4 to 5 days.

Solicited systemic adverse events were less common than injection-site events, with 54.9% of patients in the vaccine group reporting such events following the first dose, and 79.4% reporting the events following the second dose. In the placebo group, solicited systemic adverse events were reported in 42.2% of patients after the first dose and 36.5% of patients following the second dose.

Unsolicited adverse event reports were similar in both groups. A total of 5 deaths were reported between the placebo and vaccine groups. Of the 2 deaths reported in the vaccine group, one was due to cardiopulmonary arrest and the other was a suicide.

Grade 3 adverse events were reported in 1.3% of patients in the placebo group and 1.5% of patients in the vaccine group. Medically attended adverse events occurred in 9.7% of the placebo group and 9.0% of the vaccine group, and serious adverse events occurred in 0.6% of both groups.

“Overall, the safety of the mRNA-1273 vaccine regimen and platform is reassuring,” wrote corresponding author Hana M. El Sahly, MD, of the Baylor College of Medicine, and colleagues. “[N]o unexpected patterns of concern were identified.”

The authors said the data must be put in context, coming amid shifting infection trajectories over the summer, and in an environment where many local governments were requiring social distancing, mask-wearing, and other infection-control tactics. The investigators said the fact that none of the severe cases of COVID-19 were reported in the vaccine group is an encouraging finding. The research team will continue collecting follow-up data and assessing changes in efficacy over time, as the study is ongoing.

Newly published data shows just 0.6% of patients receiving the Moderna mRNA vaccine reported serious adverse events, a rate identical to that of the placebo group.

Moderna Vaccine Study Data Shows 94.1% Efficacy; Serious Side Effects Rare

A new multiplex polymerase chain reaction (PCR) panel was able to match the performance of quantitative bacterial culture and provide greater specificity, according to a new study.

The findings raise the possibility for significantly faster, and more accurate, diagnosis of lower respiratory tract infections (LRTIs). The report was 

Corresponding author Matthew D. Sims, MD, PhD, of Beaumont Hospital, in Michigan, and colleagues, wrote that quantitative bacterial culture of bronchoalveolar lavage (BAL) fluids is a lengthy process, and its sensitivity is relatively low, particularly when the patient has had prior antimicrobial therapy. As a result, many patients are empirically 

prescribed broad-spectrum antibiotics, a problem that contributes to antibiotic resistance

. The investigators said an improvement in testing could lead to a significant improvement in patient care.

“Early diagnosis and proper choice of antimicrobials are crucial for successful management of pneumonia,” they wrote.

The new panel, called the Unyvero LRT BAL leverages molecular diagnostics and bioinformatics to detect 19 bacteria, 10 antibiotic resistance markers, and the fungus 

An earlier study found the panel performed well compared to quantitative bacterial culture in a study of 175 specimens. This new study was designed to verify those results, using 1400 patient samples from 11 clinical trial sites.

The majority of the samples (1016) were collected prospectively within 24 hours of arrival at 9 US hospitals. Another 392 archived specimens were also included in the study. The samples were collected between 2015 and 2018 at 2 additional US hospitals.

The investigators found an overall positive percent agreement (PPA) between the Unyvero panel and BAL culture of 93.4%, and a negative percent agreement (NPA) of 98.3.

, the investigators found a 100% (5/5) PPA and a 99% (99/100) NPA. That’s a particularly meaningful result, they wrote, because 

 pneumonia is often not considered as a potential diagnosis; they said the Unyvero panel is the only US Food and Drug Administration (FDA) approved panel to offer such testing, and therefore might allow for more comprehensive diagnosis of this particular type of pneumonia.

The study also was better able to detect numerous other clinically relevant pathogens in a rapid manner, which Sims and colleagues said could make it easier for physicians to choose the 

, allowing them to better align with antibiotic stewardship goals.

In a press release, Faranak Atrzadeh, MA, chief marketing and scientific affairs officer of the panel’s developer, OpGen Inc., said microbiological confirmation of severe pneumonia is “a crucial step” for tailoring antibiotic therapy.

“Unyvero LRT panels are culture-independent and provide the speed and sensitivity that may achieve more reliable identification of causative agents than culture, allowing clinicians to make more informed decisions about antibiotics use,” she said.

In terms of antibiotic resistance, the authors compared the panel’s antibiotic resistance marker results to standard antibiotic susceptibility testing and found positive predictive values of 80-100%, depending on the particular microorganism and specific resistance marker.

The FDA approved the Unyvero LRT panel for use with BAL samples back in January.

A new multicenter study confirms earlier findings that the panel performs well against the more time-intensive quantitative bacterial culture.

Multiplex PCR Panel Provides Faster, Accurate Lower Respiratory Tract Infection Diagnosis

As the COVID-19 pandemic nears its one-year anniversary and nations around the world rush to vaccinate their populations, public health officials are sounding the alarm about the possible psychiatric impacts of the vaccine.

Journal of the American Medical Association

, corresponding author Emma E. McGinty, PhD, of the Johns Hopkins Bloomberg School of Public Health, and colleagues, report on their findings when they surveyed more 1,337 adults about their 

 in the spring and summer months of the coronavirus disease 2019 (COVID-19) pandemic.

The survey respondents were drawn from the NORC AmeriSpeak panel of 35000 US adults over the age of 18. An initial survey was conducted in April, and a follow-up in July. The survey measured psychological distress for the 30 days prior to the survey using the Kessler 6 scale.

They found the prevalence of serious psychological distress (a score of 13 or higher on the 0- to 24-point Kessler scale) was 13.6% in April 2020 and 13.0% in July of 2020. That compares to a rate of just 3.9% in April 2019.

Young adults (ages 18-29) had the highest prevalence of psychological distress of any age group, with roughly a quarter of respondents in that age group reporting serious distress. Those with incomes of less than $35000, and Hispanic individuals also reported high rates of psychological distress, 21.2% and 19.2% in July, respectively.

high prevalence of psychological distress

, McGinty and colleagues said the fact that the high rate of distress appears to be persisting over time is also worrisome, since persistent distress increases the risk of psychiatric disorders.

In the survey, 72% of adults who reported serious distress in July had also reported serious distress in April.

 that it will likely be a while before the psychiatric impacts of COVID-19-related distress are fully known. She said some patients might already be experiencing conditions like depression and anxiety as a result of COVID-19-related distress, but in other patients the effects might develop over time as a result of cumulative distress.

“It also often takes time for people to seek treatment (and you can’t be diagnosed until you seek treatment),” she noted, “so there may be a lag for that reason as well.”

For primary care physicians, the data present an additional challenge – identifying patients whose pandemic-related stress might be leading to more serious psychiatric outcomes. She said physicians can use the Kessler 6 screening tool, the Generalized Anxiety Disorder screening instrument, 7-item (GAD-7), and others to help find patients who might warrant psychological or psychiatric follow-up.

Unfortunately, the physicians can only provide such assistance if the patient shows up in a clinic. And the study’s results indicate that access to care can be a challenge for many of the people most at risk for psychological distress during the pandemic.

McGinty and colleagues found 35% of adults with serious distress said one factor contributing to their stress was an inability to obtain healthcare. The authors concluded that this data point underscores the importance of access to care, not only during pandemics, but all of the time.

New research finds the rate of psychological distress among US adults remained more than 3 times higher than normal in the early months of the pandemic.