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HIV preexposure prophylaxis (PrEP) has a critical role in ending the HIV epidemic in the United States. This article will explore the current state of HIV PrEP uptake in this country and describe measures that can help to both increase awareness of HIV PrEP and improve adherence to this important prevention strategy.

High-risk behaviors related to, and populations affected by, HIV infection

In the United States, an estimated 1.2 million people aged 13 years or older were living with HIV in 2019; an estimated 13.3% of these patients, however, had not received a diagnosis.

 Behaviors that increase the risk of acquiring HIV infection include sexual activity with an infected person and injection of illicit drugs.

 Individuals who inject illicit drugs and have an HIV-positive injecting partner or share injection equipment are at highest risk of HIV acquisition.

Although HIV infection can occur in persons of any age, gender, race, ethnicity or sexual orientation, HIV disproportionately affects gay and bisexual men and other men who have sex with men (MSM) in the United States.

 Members of racial and ethnic minority communities are also highly affected. In the United States, 42.1% of new HIV infections occurred in Black populations in 2019, a rate that was more than eight times higher than that reported among White populations (5%).

 Individuals with Hispanic/Latino ethnicity comprised 21.7% of newly infected people.

HIV PrEP involves taking medication to prevent HIV infection. Clinical practice guidelines issued in 2021 by the Centers for Disease Control and Prevention (CDC) recommend informing all sexually active adults and adolescents about HIV PrEP, screening all sexually active patients for an HIV PrEP indication and screening all adult patients for use of injectable illicit drugs. The guidelines also recommend that clinicians discuss HIV PrEP with sexually active patients and prescribe it to those who are at risk of HIV infection or who request a prescription. Similarly, clinicians should prescribe HIV PrEP to patients who inject illicit drugs and are at risk for acquiring HIV or who request it.

Two drug combinations are recommended by the CDC for oral HIV PrEP.

 In 2012, Truvada, a combination pill composed of emtricitabine and tenofovir disoproxil fumarate (F/TDF), became the first FDA-approved HIV PrEP agent.

 Daily F/TDF is indicated for adult and adolescent men and women weighing at least 35 kilograms; its use is recommended for those who report either illicit drug injection or sexual practices that place them at risk of acquiring HIV infection.

 Another oral pill, Descovy, gained FDA approval for HIV PrEP in 2019.

 This combination of emtricitabine and tenofovir alafenamide (F/TAF) is indicated for daily oral use in transgender women and in sexually active men or adolescents weighing at least 35 kilograms; it is also recommended for those who report sexual practices that place them at risk of acquiring HIV.

 The effectiveness of F/TAF has not been studied in individuals at risk of HIV infection from receptive vaginal sex, so it is not recommended in this population.

In December 2021, the FDA approved the first injectable option for HIV PrEP.

 Apretude (cabotegravir; CAB) is a long-acting, injectable drug indicated for adults and adolescents who weigh at least 35 kilograms; its use is recommended in those who report sexual practices that place them at risk of acquiring HIV.

 The CDC recommends that CAB be given, as indicated, every two months by injection into the gluteal muscle with an optional oral four-week lead-in.

 Intramuscular (IM) CAB therapy may be appropriate for patients who have significant renal disease, difficulty in adhering to oral HIV PrEP or a preference for receiving injections every two months versus using oral PrEP.

 For patients taking oral HIV PrEP, laboratory tests recommended before or during PrEP use include estimated creatine clearance, hepatitis B-virus serology and lipid panel testing; however, these tests are not required for patients taking CAB for HIV PrEP.

 Unlike oral HIV PrEP medications, CAB can be taken by patients with severe renal impairment or end-stage renal disease.

IM CAB was evaluated in clinical studies that involved a wide range of participants, including cisgender women (HPTN 084; NCT03164564) and cisgender MSM and transgender women who have sex with men (HPTN 083; NCT02720094).

HPTN 083 was a phase 2b/3, international, multicenter, double-blind, randomized controlled trial (RCT) that examined the safety and efficacy of IM CAB injection administered every eight weeks versus daily oral F/TDF given to adult cisgender MSM and transgender women who have sex with men. Incidence of HIV infection was lower in the CAB arm (n = 2,282) than in the F/TDF arm (n = 2,284; 0.41 vs. 1.22 per 100 person-years, respectively), and the risk of infection was 66% lower in the CAB arm than in the F/TDF arm (hazard ratio, or HR, 0.34; 95% confidence interval, or CI, 0.18-0.62; p-value < .001). The safety population included 4,562 patients (CAB arm, 2,280 patients; F/TDF arm, 2,202 patients). In this population, 92.5% reported side effects of grade two or higher, 32.7% reported side effects of grade three or higher and 5.3% reported serious side effects, with similar frequencies of events noted across the two groups. Among patients who received active CAB injections, 2.4% of patients (50 of 2,117 patients) discontinued injections because of injection-related side effects.

HPTN 084 was an RCT that evaluated IM CAB versus oral F/TDF given in three phases to 3,224 sexually active cisgender women.

 Among the 1,614 women in the CAB arm, the incidence of HIV infection was lower (0.2 per 100 person-years; 95% CI, 0.06-0.52) than that recorded among the 1,610 women in the F/TDF arm (1.86 per 100 person-years; 95% CI, 1.3-2.57).

 Overall, women in the CAB group had an 89% lower risk of HIV infection than did women in the F/TDF group (HR, 0.11; 95% CI, 0.01-0.31; p-value = .000027). Any site reaction was experienced by 32% of patients in the CAB arm and 9% of patients in the F/TDF arm; reactions of grade two or higher were noted among 7% and 1% of patients, respectively, and there were no discontinuations due to injection-site reactions in either study arm.

Adherence to oral HIV PrEP is critical to prevent HIV acquisition.2 For patients who may struggle to achieve high adherence to oral HIV PrEP, IM CAB provides an alternate option. Rather than taking a daily pill, patients need to receive only one injection of CAB every two months. The results of clinical trials have shown that IM CAB provides 66% to 89% higher efficacy than does oral F/TDF.

In 2019, substantial evidence that PrEP could reduce risk of HIV acquisition via sexual activity or illicit drug injection led to a U.S. Preventive Services Task Force (USPSTF) A rating for the recommendation that it be offered to persons at high risk of HIV infection.

 The USPSTF guidelines are currently being updated, and injectable CAB was not yet approved by the FDA when the 2019 version was released. According to the provisions of the Affordable Care Act (ACA) part 47, this A rating requires most insurers to cover PrEP with no cost-sharing.

 No-cost coverage must include not only medication but also counseling (including for adherence, risk reduction and mental health counseling) and the laboratory testing and office visits necessary for initiation or continuation of PrEP use.

Per ACA part 47, plans and issuers are allowed to employ reasonable medical management techniques regarding HIV PrEP coverage, which may include no-cost coverage of generic PrEP but imposition of cost-sharing on the equivalent branded version. If a patient’s healthcare provider deems use of the covered drug to be medically inappropriate, plans and issuers must provide a mechanism to waive cost-sharing for a more appropriate medication.

 For individuals who lack prescription drug coverage, the U.S. Department of Health and Human Services has made F/TDF and F/TAF available free of charge through the Ready, Set, PrEP program.

PrEP uptake: Current status, barriers and opportunities

As of 2018, of nearly 1.2 million people in the United States who had indications for HIV PrEP therapy, only approximately 220,00 individuals received a prescription.

 The reasons for this relatively low uptake of HIV PrEP are multifactorial. A review of literature published from 2016 to 2019 identified the following key barriers: low awareness of HIV PrEP among providers and patients, especially those individuals at risk for or living with HIV; low perception of personal HIV risk; social stigma associated with PrEP use; provider bias (whether implicit racial/ethnic prejudice or bias against LGBTQ+ patients); patient distrust of the healthcare system; lack of access to medical care or financial assistance; and provider and patient concerns about side effects and medication interactions.

One method for increasing uptake of HIV PrEP is to facilitate discussion of PrEP between healthcare providers and patients.

 This includes taking sexual histories of patients, which can help identify patients who are at risk for HIV infection and who may benefit from HIV PrEP. This method also includes providing information about PrEP so patients can respond openly to risk assessment questions and discuss PrEP with others who may benefit from its use.

To promote adherence, providers should establish trust and bidirectional communication with their patients who start HIV PrEP. Providers should stress the need for adherence, educate patients on potential medication side effects, help create dosing schedules, identify and address barriers to adherence, and monitor HIV PrEP adherence in a nonjudgmental manner. A multidisciplinary approach can also help. The 2021 CDC PrEP guidelines emphasize that a care team of healthcare professionals (e.g., physicians, nurses, pharmacists) working together can improve a patient’s HIV PrEP medication adherence.

PrEP has a critical role to play in ending the HIV epidemic in the United States. Efforts should be focused on preventing infection via expanded awareness of, and access and adherence to, HIV PrEP for everyone at risk of sexual or injection-acquired infection. The 2021 FDA approval of an injectable option for HIV PrEP provides clinicians and patients with an effective therapeutic choice that does not require remembering to take a pill every day. In addition, to promote widespread HIV PrEP use, it is crucial to address barriers that contribute to lack of patient access or withdrawal from PrEP care.

. Centers for Disease Control and
Prevention. May 2021. Vol. 26(1). Accessed March 23, 2022.
https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report-vol-26-1.pdf

US Public Health Service. Pre-exposure prophylaxis for the prevention of HIV infection in the United States—2021 update: a clinical practice guideline. Centers for Disease Control and Prevention. December 2021. Accessed February 28, 2022. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf

. Centers for Disease Control and Prevention. May 27, 2021. Vol. 32. Accessed March 23, 2022. https://www.cdc.gov/hiv/library/reports/hiv-surveillance/vol-32/index.html

Final recommendation statement: prevention of human immunodeficiency virus (HIV) infection: preexposure prophylaxis. US Preventive Services Task Force. Updated January 6, 2022. Accessed March 23, 2022. https://www.uspreventiveservicestaskforce.org/uspstf/
recommendation/prevention-of-human-immunodeficiency-virus-hiv-
infection-pre-exposure-prophylaxis

U.S. Food and Drug Administration approves Gilead’s Truvada for reducing the risk of acquiring HIV. News release. Gilead Sciences. July 16, 2012. Accessed March 24, 2022. https://www.gilead.com/news-and-press/press-room/press-releases/2012/7/us-food-and-drug-administration-approves-gileads-truvada-for-reducing-the-risk-of-acquiring-hiv

Truvada. Prescribing information. Gilead Sciences; 2020. Accessed March 24, 2022. https://www.gilead.com/~/media/files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. News release. Food and Drug Administration. October 3, 2019. Accessed March 24, 2022. https://www.fda.gov/news-events/press-announcements/
fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic

Descovy. Prescribing information. Gilead Sciences; 2022. Accessed March 25, 2022. https://www.gilead.com/-/media/55b14ac03ef94b6f98d5d3c31ea0137b.ashx

FDA approves first injectable treatment for HIV pre-exposure prevention. News release. Food and Drug Administration. December 20, 2021. Accessed March 24, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-
treatment-hiv-pre-exposure-prevention

Apretude. Prescribing information. ViiV Healthcare; 2021. Accessed March 25, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Apretude/pdf/APRETUDE-PI-PIL-IFU.PDF

Delaney-Moretlwe S, Hughes JP, Bock P, et al; HPTN 084 Study Team. Long acting injectable cabotegravir is safe and effective in preventing HIV in cisgender women: interim results from HPTN 084. 2021. Presented at: HIVR4P Conference; January 27, 2021; virtual. Accessed March 25, 2022. https://programme.hivr4p.org/Abstract/Abstract/1479

Landovitz RJ, Donnell D, Clement ME, et al; HPTN 083 Study Team. Cabotegravir for HIV prevention in cisgender men and transgender women.

. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016

FAQs, Affordable Care Act Implementation Part 47.
Department of Labor. July 19, 2021. Accessed March 30, 2022. https://www.dol.gov/sites/dolgov/files/EBSA/about-ebsa/our-activities/resource-center/faqs/aca-part-47.pdf

Mayer KH, Agwu A, Malebranche D. Barriers to the wider use of pre-exposure prophylaxis in the united states: a narrative review. 

. 2020;37(5):1778-1811. doi:10.1007/s12325-020-01295-0

Articles

Opportunities for identifying and addressing barriers to HIV PrEP 

Patients with myeloproliferative neoplasms (MPN) appear to respond well to SARS-CoV-2 vaccination, according to a new report, with patients demonstrating high serologic and T-cell responses to the two most commonly administered vaccines.

, M.D., of Harvard Medical School, and colleagues, said while the SARS-CoV-2 vaccines developed by Moderna and Pfizer are widely successful at producing neutralizing antibodies in most adults, the vaccines have produced less robust immunologic responses in patients with hematologic malignancies.

Patients with MPNs “are immunocompromised due to impaired innate and adaptive immunity, heightened inflammation, and effects of ongoing treatment,” How and colleagues said. “As a result, patients are at high risk for complications related to SARS-CoV-2 infection.”

Given the novelty of the virus, the investigators wanted to get a better understanding of how the vaccines performed in real-world people with MPNs. They noted that most previous reports on vaccine protection in patients with hematologic malignancies focused on quantifying anti-spike antibodies. But they said T-cell responses are also a key metric for understanding immune response to vaccination.

“In particular, neutralizing antibody activity is significantly reduced against SARS-CoV-2 variants after vaccination, although T-cell responses still appear to be intact,” they wrote. “T-cell responses are therefore particularly important to prevent severe COVID-19 caused by emerging variants such as Omicron.”

The investigators recruited 21 patients with MPN who had baseline blood samples collected, completed vaccination with either the Moderna or Pfizer vaccines, and had a second blood sample taken one month following vaccination. Seven additional patients were included in the analysis despite having only a post-vaccination blood sample, and not a pre-vaccination sample. The authors used data from 26 vaccinated patients with no history of active malignancy as their control group. At baseline four of the 21 MPN patients had positive serology tests for SARS-CoV-2, and 3 patients had a known history of infection.

In both the MPN group (21 patients plus the additional seven patients), all but one vaccine recipient had evidence of positive serology a month after vaccination. The only patient who did not was on ruxolitinib (Jakafi). Similarly, 25 of the 26 patients in the control group had positive serology after a month.

“In the four MPN patients who had positive baseline serology, post-vaccination concentrations appeared similar to that of MPN patients without SARS-CoV-2 exposure,” the authors said.

How and colleagues also used two interferon γ-release assays to assess T-cell responses one month following vaccination.

On one of the assays, the ELISpot assay, positive responses greater than 90% were reported in both the MPN and control groups. However, the investigators also found that patients with MPNs tended to have lower anti-Spike immunoglobulin G concentrations, “which may indicate a less robust serological response,” they said.

Furthermore, the authors said, there appeared to be a signal for lower immunological responses in T-cell assays of patients with myelofibrosis, though the authors noted that that sample size was small, as just eight patients with myelofibrosis were included in the analysis. They added that age, but no other variables, seemed to have an effect on T-cell response.

How and colleagues said there were other subtle differences between the two groups, which may warrant further investigation. They concluded by noting that their samples may not necessarily reflect actual infection rates.

“Prospective studies with endpoints of clinical infection would be necessary to understand how immune responses to vaccines translate to reduction of COVID-19 cases,” they said.

Data suggest most patients have positive serology results a month following vaccination with either the Moderna or Pfizer vaccine.

Analysis Suggests Patients with MPN Benefit from COVID-19 Vaccination

Severe asthma is categorized based on patients’ response to treatment and the presence of biomarkers, such as immunoglobulin E (IgE), eosinophils, and neutrophils. Allergic asthma, eosinophilic asthma, and non-eosinophilic asthma are types of severe asthma. Patients with allergic asthma typically have high levels of IgE when exposed to allergens. People with eosinophilic asthma have increased eosinophil levels, and those with noneosinophilic asthma show neither increased IgE nor eosinophil levels. But they may have high neutrophil levels.

The presence or absence of these biomarkers has made targeted treatment possible for certain types of severe asthma but elusive for others. Biologics that target cytokines directly involved in IgE or eosinophil activity are helpful in treating allergic asthma and eosinophilic asthma. These agents, however, fail to address the treatment needs of patients with non-eosinophilic asthma. In fact, there exists a scarcity of treatment for this type of asthma.

Noneosinophilic asthma, also called non-type 2 inflammation, does not respond to treatment with inhaled corticosteroids or most biologics FDA-approved to treat other types of severe asthma. Scientists know that bacterial exposure can trigger lung inflammation characteristic of non-eosinophilic asthma but have struggled to understand the link between the two.

Senior scientific researcher Dr. Sarah Headland and colleagues at Genentech Immunology Discovery have discovered a protein that may help solve the puzzle. In 

 in January of this year, Headland and colleagues identified oncostatin M as a protein responsible for the severe airway inflammation seen in patients with noneosinophilic asthma.

The researchers compared airway biopsies from patients with severe asthma, mild to moderate asthma, and individuals without asthma. They found that patients with severe asthma had uncommonly high oncostatin M activity compared to those in the other two groups. The researchers also found that bacterial cell wall component lipopolysaccharide induces oncostatin M activity in patients with non-eosinophilic asthma.

These findings may be promising in terms of developing treatment specific for non-type 2 inflammation in severe asthma. Using the results from this research, South San Francisco-based Genentech is developing a monoclonal antibody to potentially block oncostatin M and prevent airway inflammation in this type of asthma. Experiments have been limited to animal models, but the company intends to create a product for testing in human clinical trials. In collaboration with Novartis, Genentech also developed Xolair (omalizumab), an anti-IgE antibody FDA-approved to treat moderate to severe allergic asthma in adults and children 6 years or older.



Genentech researchers identify oncostatin M as a protein that may be responsible for the severe airway inflammation seen in patients with noneosinophilic asthma.

New Target Discovered for Non-Type 2 Inflammation in Severe Asthma

Though the understanding of sleep has been grown in recent years, investigators say a potentially valuable sleep-related biomarker has been hiding right beneath our eyelids.

, a team of neurologists and sleep experts argue that the frequency of eye movements during rapid eye movement (REM) sleep deserves more attention as a potential biomarker for a range of diseases and conditions.

 of the University of Basel, and colleagues, began making their case by outlining the growth of research into 

. They noted that rapid eye movements were first linked with the generation of ponto-geniculo-occipital waves more than 50 years ago. More recently, though, REM density (the measure of rapid eye movement frequency) was linked with increased metabolic activity in the right geniculate body and the primary occipital cortex. In 2015, Saleh and colleagues said, investigators used neuroimaging to identify deep brain activation in several parts of the brain during REM sleep.

Collectively, those studies paint an intriguing picture, the authors said.

“As REMs [rapid eye movements] can be linked with circuitries directly or indirectly related to the ponto-geniculo-occipital wave generation during REM sleep, it becomes a timely topic or opportunity to reconsider if abnormalities in REMs may reflect disease involvement of these structures associated with specific syndromes or disorders,” Saleh and colleagues said.

Already, the investigators said, abnormal REM density (RD) has been associated with conditions like narcolepsy, depression, and borderline personality disorder, among others.

They said patients with elevated REM density have been found to have more severe depression and worse clinical outcomes compared to peers with lower REM density.

REM density may also to play a role in alcohol dependence.

“In a study examining the likelihood of alcohol relapse, increased RD (REM density) at admission to an alcohol rehabilitation facility predicted alcohol relapse at 3 months,” Saleh and colleagues noted.

There is also evidence to suggest REM density might be important in diseases such as narcolepsy and Parkinson’s disease, but the investigators said many of the existing studies have not taken it into account.

For example, a 2020 study suggested patients with Parkinson’s disease had reduced REM density compared to healthy controls. Yet, many other studies do not even include REM density as a parameter.

“Of note, in a meta-analysis of 50 studies with [polysomnography] data in Parkinson’s disease, only one study reported RD (REM density) data even though pathological findings on other parameters of REM sleep macrostructure such as REM latency and total REM sleep time have frequently been analyzed,” Saleh and colleagues said.

The investigators argue that sufficient associations have been identified to justify a broad expansion of REM density and its relationship with other diseases. However, they said one barrier to expanding REM density research is a lack of consensus about how best to define it.

“For example, should RD (REM density) be reported as a frequency of REMs per minute of REM sleep, RD (REM density) count for each REM sleep episode, or by other definitions using specific computational methods?” they wrote. “And furthermore, which REM sleep episode is best to evaluate for RD (REM density)?”

The authors said a number of pressing questions remain to be explored with regard to REM density and what it says about a person’s neurology and health. If a clear definition and clear parameters were adopted, polysomnography could be used to easily obtain REM density readings and perhaps a better understanding of a patient’s neurological and psychiatric disorders, they concluded.

“Ultimately, RD (REM density) may qualify as a valid, easily obtainable biomarker for both diagnostic precision and prognosis,” they wrote, “thus potentially ushering in earlier and more efficient treatment management plans.”

The frequency of rapid eye movement appears to be associated with several psychiatric and neurological disorders, investigators said.

REM Density Could Be Potent Biomarker, Investigators Argue

Lack of sleep appears to be associated with the risk of nonalcoholic fatty liver disease (NAFLD), according to a new study, but “catch-up” sleep amy lower the risk.

The findings could help scientists better understand NAFLD and the implications of sleep on the disease. The report was 

NAFLD is a broad term for a wide variety of conditions caused by the excessive accumulation of fat. It comes with an increased risk of other metabolic conditions, such as diabetes and obesity.

Sleep — and sleep duration, in particular — is increasingly being identified as playing a role in a number of chronic conditions, wrote corresponding author Sangheun Lee, Ph.D., of the Catholic Kwandong University College of Medicine in South Korea. Recent evidence suggests the risk of NAFLD may be itself affected by sleep.

“Insufficient sleep, as well as poor sleep quality, can trigger several pathophysiological processes that are associated with NAFLD,” the authors noted.

Yet Lee and colleagues said while a broad association between NAFLD and sleep duration has been studied, there is less of an understanding of how certain sleep patterns affect (or potentially cause) NAFLD. One sleep pattern — weekend catch-up sleep (WCUS) — is an increasingly common behavior, the authors said. The term refers to the pattern of getting insufficient sleep during the workweek, but then sleeping for extra long periods of time on weekends in order to catch up.

The investigators decided to examine data from the Korea National Health and Nutrition Examination Survey, a survey that involved more than 100,000 patients in South Korea who enrolled between 2008 and 2019.

Survey respondents were grouped into three categories: patients who slept for less than seven hours per night on average; patients who slept for less than seven hours per night on weeknights, but more than seven hours per night on weekends; and patients who slept more than seven hours per week, on average.

The investigators found a significant negative relationship between sleeping more than seven hours per night and risk of NAFLD. Using a hepatic steatosis index (HSI) score of 36 or higher as an indicator of a fatty liver, the investigators found patients who got less than seven hours of sleep were significantly more likely to have fatty livers. When the authors used a more recent subset of the data (one that included weekend sleep behavior), they found the same association. The finding was true for both male and female subjects.

Lee and colleagues said there are several possible reasons for the relationship between NAFLD and sleep. They noted that the hypothalamic-pituitary-adrenal axis and the autonomic nervous system are key to the regulation of physical and mental health.

“Cortisol, inflammatory cytokines, and norepinephrine, which are derivatives of these systems, are associated with the variation in sleep such as total sleep time, sleep quality, sleep efficiency, and circadian midpoint,” the authors wrote. “The dysregulation of this axis caused by changes in sleep can increase the risk of NAFLD onset.”

They added that sleep duration is tied to leptin concentration, and leptin is associated with metabolic disease.

“A decrease in sleep duration results in a decrease in leptin concentration and an increase in the activity of the food reward system,” they said. “This leads to an increase in calorie intake and weight gain.”

Lee and colleagues noted that seven hours or more of sleep on weekdays and weekends and having WCUS were negatively correlated with obesity in the study.

However, the investigators said it is not clear whether “catch-up” sleep can ameliorate the increased risk of NAFLD.

“No research has shown how WCUS relieves the fatty liver in animal experiments and other clinical studies, however, we have suggested that sleep supplementation during weekends may ease oxidative stress and inflammation in the liver,” they wrote.

Lee and colleagues concluded that additional research should be done to find out the causal relationship, if any, between NAFLD and sleep. They said such research could lead to an expansion of therapeutic options for NAFLD, which are currently limited to weight loss and improving eating habits.



Using a data set of more than 100,000 people, investigators found getting more than seven hours of sleep per night reduced the risk of developing fatty liver disease.

Sleep Linked to Protection Against Nonalcoholic Fatty Liver Disease

In 2018, Sanofi and Regeneron Pharmaceuticals were granted 

 as add-on treatment for moderate to severe eosinophilic asthma. The approval was based on positive results from three pivotal randomized clinical trials evaluating the safety and efficacy of Dupixent in adults and adolescents with moderate to severe eosinophilic asthma. Results from the trials demonstrated that Dupixent significantly improved lung function and reduced severe exacerbations compared to placebo. Additionally, Dupixent reduced the average daily use of oral corticosteroids by a higher percentage than placebo (70% versus 42%).

 in April of this year retrospectively evaluated the efficacy of Dupixent in the treatment of severe asthma in a real-world setting. The study, conducted at 

 in Tokyo, looked at 26 adults who received Dupixent treatment for severe asthma from April 2019 through December 2021. The primary endpoints were the change in the number of annual asthma exacerbations and the reduction in the use of oral corticosteroids at the last follow-up as measured in prednisone equivalents.

Of the 26 participants, 16 had switched to Dupixent after having previously used a different biologic for severe asthma treatment.

The study found that Dupixent significantly reduced the number of annual severe asthma exacerbations by 53% and the mean dose of daily oral corticosteroid use significantly decreased by 54%. These real-world results are comparable to those observed in major randomized clinical trials. However, the Japanese study also observed that adverse events associated with high eosinophil levels were more prominent in patients who had switched from a different biologic before starting Dupixent versus those who were biologic naïve before treatment with Dupixent. One patient who changed from Nucala (mepolizumab) discontinued Dupixent treatment due to hypereosinophilia. Another patient, who had been previously using 

 (benralizumab), discontinued Dupixent treatment due to a relapse of chronic eosinophilic pneumonia.

Because of these findings, the study authors suggest monitoring eosinophil levels during Dupixent treatment in patients who switch from other biologics. “Compared to biologic-naïve patients, we propose that long-term careful observation for one year be necessary when patients shift biologics from anti-IL-5/IL-5R antibody to dupilumab”, the authors recommend.

This study was a small, single-center, retrospective study. Despite these limitations, the authors believe that the study population adequately reflects a real-world setting in Japan and conclude that Dupixent is effective in the real world in reducing severe asthma exacerbations and decreasing the use of oral corticosteroids in patients with severe asthma.

Real-world study conducted in Japan shows Dupixent (dupilumab) reduced the number of annual severe asthma exacerbations by 53%. There were some reports of adverse events associated with high eosinophil levels in patients who switched to Dupixent after taking a different biologic.

Dupixent Improves Severe Asthma Symptoms in a Real-World Setting, but Switching May Require Eosinophil Monitoring

Patients undergoing treatment for gynecological cancer commonly experience sleep disturbances, but a new review article suggests there are a number of strategies available that can help improve patients’ sleep before, during and after treatment..

International Journal of Gynecological Cancer

It outlines research related to sleep in gynecological cancers, but also in other types of cancer, such as breast cancer.

The major external culprit in sleep disturbance among women with gynecological cancer is pain, explained corresponding author Emma L. Barber, of the Northwestern University Feinberg School of Medicine, and colleagues.

“Previous studies have shown that pain causes the largest reduction in sleep duration because it is the most likely to persist throughout the night,” Barber and colleagues wrote. “Sleep and pain furthermore have a bidirectional relationship where sleep disruption can cause hyperalgesia, and pain can conversely cause sleep disruption.”

The problem of sleep disruption, however, can begin the moment a patient is diagnosed. The investigators said pretreatment sleep disturbances are often associated with depressive symptoms and anxiety. Patients with ovarian cancer tend to be more likely to have sleep disorders than patients with endometrial cancer, whose sleep disorder rates are similar to that of the general population, the investigators found.

“The most commonly cited risks of developing sleep disorders in the ovarian cancer population are abdominal discomfort and high distress at time of diagnosis,” they wrote.

During treatment, patients who undergo chemotherapy or radiation may have levels of physical fatigue that interfere with sleep quality, but they can also suffer from side effects like nausea and vomiting, which can affect sleep.

One study found 24% of patients with ovarian cancer who underwent palliative chemotherapy had sleep disturbances. Another study suggested that up to 80% of patients with gynecological cancer experienced sleep disruptions while hospitalized.

Even after treatment, many patients find themselves having difficulty sleeping. Barber and colleagues noted that sleep deprivation can slow patients’ recovery from surgery and lead to longer hospital stays.

However, the investigators said a number of tools are available to address the problem. Strategies like cognitive behavioral therapy for insomnia (CBT-I), sleep-schedule regulation, and limitation of caffeine can help patients prior to treatment, as can pharmacological products like zolpidem (Ambien), benzodiazepines, or melatonin.

During treatment, the investigators said CBT-I and exercise therapy have been shown to be the most effective interventions against sleep disturbances, but they added that management of side effects is also important.

While patients are hospitalized following treatment, the authors said literature supports the use of eye masks and earplugs to block light and noise. They said hospital staff should work to limit disruptions and interruptions at night. Pharmacological solutions are also useful, though the authors said benzodiazepines are typically avoided due to the risk of dependence.

Once a patient is discharged, the authors said many of the earlier strategies, such as CBT-I and exercise therapy, should be considered to help limit long-term sleep problems.

While their review centers on the causes and consequences of sleep disturbances, the authors said the inverse is also true.

“Conversely, good sleep in survivors is linked with a more positive affect and fewer episodes of anxiety or depression,” they wrote. “Because of the difference sleep quality poses to outcomes and patient quality of life, patient sleep at diagnosis, during treatment, and after treatment must be addressed.”

Barber and colleagues said physicians should regularly assess their patients for sleep disturbances, something that can be accomplished with tools such as the General Sleep Disturbance Scale. When problems are identified, they said, it is critical for physicians to intervene.

“Many of these interventions are easily implemented at a low cost, or no cost, and may benefit patients with gynecological cancers,” they said.

Treatments like cognitive behavioral therapy for insomnia and exercise therapy can help address sleep problems, both during and after treatment, the study found.

Sleep Disturbances a Major Issue in Gynecological Cancer, Review Finds

The FDA has launched a new program that is aimed to increase the development of drugs for people with rare diseases. Called Accelerating Rare Disease Cures (ARC), the 

 is managed by Center for Drug Evaluation and Research’s (CDER) Rare Diseases Team and will provide coordination across the agency’s efforts in this area.

This new effort continues the regulator agencies effort to provide support for the development of rare diseases. One effort, developed in collaboration with the Critical Path Institute, is the Rare Disease Cures Accelerator-Data and Analytics Platform. The platform provides a database designed to promote the secure sharing of existing patient-level data and encourage the standardization of new data collection.

FDA approves Olumiant for new COVID-19 indication.

 a new indication for Eli Lilly and Incyte’s Olumiant (baricitinib) for COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

Olumiant is the first immunomodulatory treatment for COVID-19 to receive FDA approval, the FDA said in a news release.

The agency first issued an emergency use authorization (EUA) in November 2020 for Olumiant in combination with remdesivir to treat COVID-19 in hospitalized adults and pediatric patients. In July 2021, the FDA revised the EUA to authorize Olumiant as a stand-alone treatment.

Olumiant remains under EUA status for hospitalized pediatric patients 2 to less than 18 years of age requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.

Due to the risk of blood clots, the FDA is limiting the authorized use of the Janssen COVID-19 vaccine. Now, the use of the vaccine is limited to people 18 years of age and older for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, the FDA said in a 

After conducting an updated analysis, evaluation and investigation of reported cases, the FDA has determined that the risk of thrombosis with thrombocytopenia syndrome (TTS), a rare syndrome of potentially life-threatening blood clots in combination with low levels of blood platelets with onset of symptoms.

 Radicava ORS (edaravone) oral suspension for the treatment of adults with amyotrophic lateral sclerosis (ALS). Radicava ORS, developed by Mitsubishi Tanabe Pharma America, is an orally administered version of Radicava, which was originally approved in 2017 as an intravenous (IV) infusion to treat ALS.

Radicava ORS can be taken orally or administered through a feeding tube. It has the same dosing regimen as Radicava—an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.

FDA extends review time for Pompe disease therapy.

 the review by 90 days for Amicus Therapeutics’ AT-GAA, a therapeutic to treat patients with Pompe Disease, a genetic lysosomal disorder caused by deficiency of the enzyme acid alpha-glucosidase (GAA) that leads to severe muscle weakness that worsens over time.

AT-GAA contains two components: cipaglucosidase alfa, a recombinant human acid alpha-glucosidase (rhGAA) enzyme, and miglustat, a stabilizer of cipaglucosidase alfa.

The company had submitted two applications for this therapy, one for each component. This includes a biologics license application (BLA) for cipaglucosidase alfa, which has been extended to Oct. 29, 2022, and a new drug application (NDA) for miglustat, which has been extended to Aug. 29, 2022.

The FDA extended the PDUFA dates to allow additional time to review information submitted by the company as part of its ongoing reviews. The extension of the review timeline was not related to requests for any additional clinical data.

 the review of the supplemental new drug application (sNDA) for Myfembree (relugolix, estradiol, and norethindrone acetate) for the management of moderate-to-severe pain associated with endometriosis. Regulators want additional time to review information they had requested from the companies regarding bone mineral density. The extended Prescription Drug User Fee Act (PDUFA) goal date is August 6, 2022.

Developed by Myovant Sciences and Pfizer, Myfembree was approved in the United States in May 2021 for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. Data to support this indication was based on the phase 3 LIBERTY 1 and LIBERTY 2 trials, which were published in the 

In April 2022, regulators had notified the companies that there were deficiencies in the application for endometriosis indication.

Eisai completes submission of lecanemab for Alzheimer’s disease.

 the rolling submission to FDA for an accelerated approval of lecanemab, another monoclonal antibody that targets beta amyloid, to treat mild cognitive impairment in patients with early Alzheimer’s disease. Eisai has requested priority review.

Eisai is continuing with a confirmatory phase 3 study of lecanemab with almost 1,800 patients enrolled and with results expected in the fall of this year. The FDA has agreed that this trial could be used as the confirmatory study to verify clinical benefit.

The BLA submission for lecanemab is based on clinical, biomarker and safety data from the proof-of-concept phase 2b in 856 people with early Alzheimer’s disease with confirmed presence of amyloid pathology, biomarker and safety data from an open-label extension study, and blinded safety data from the confirmatory phase 3 study.

In COVID-19 news, the FDA has approved Olumiant for new COVID-19 indication, but had limited Janssen’s COVID-19 vaccine. The agency has launched a new program for rare disease drug development and approved a new oral form of ALS therapy. Regulators have also extended the review time for both a new Pompe disease therapy and the sNDA for Myfembree for endometriosis. Additionally, Eisai has completed its submission of lecanemab for Alzheimer’s disease.

FDA Updates for Week of May 9, 2022

The National Institutes of Health, or NIH, recently announced their collaboration with the World Health Organization, or WHO, and the Medicines Patent Pool to make COVID-19 health technologies available worldwide.

The announcement was made at the second Global COVID-19 Summit on May 5.

 research tools and early-stage vaccine and diagnostic candidates to the Medicines Patent Pool through WHO's COVID-19 Technology Access Pool, or C-TAP, according to an article from HealthcareFinance.

These licenses will allow international manufacturers to use the technologies for the potential development of COVID-19 vaccines, treatments and diagnostics to benefit people living in low- and middle-income countries. 

C-TAP aims to boost the global supply of vaccines, treatments and diagnostics for COVID-19 by facilitating the sharing of intellectual property, knowledge and data with quality-assured manufacturers that have the capacity to scale up production, the report said.

"Controlling COVID-19 globally and addressing future public health threats is only possible if all communities, including the most vulnerable, have access to lifesaving treatments, vaccines and diagnostics," said Health and Human Services Secretary Xavier Becerra, in the report. "Sharing our scientific knowledge and health technologies with C-TAP to foster the development of crucial medical countermeasures is another step we are taking to assist our global partners in our shared fight against this devastating disease."

The agreement will allow for greater access to these technologies with the goal of leading to the development of commercial products that can address current and future public health needs.

The partnership will allow international manufacturers to use the technologies for the potential development of COVID-19 vaccines, treatments and diagnostics to benefit people living in low- and middle-income countries. 



NIH Partners with WHO to Make COVID-19 Tech Available Worldwide

Researchers have constructed a “what if” model of vaccination rates to calculate how many deaths might have been prevented if COVID-19 vaccination rates were higher.

 issued by the Brown University School of Public Health and Microsoft AI for Health, show 318,981 deaths from COVID-19 could have prevented from Jan. 1, 2021, through April 30,2022, assuming that each state continued to vaccinate at its peak rate till 100% of their adult population was vaccinated. Using that assumption, they calculate that 50% of the 641,305 deaths could have been prevented.

If the peak rate continued till 90% of the adult population was vaccinated, then 225,427 deaths would have been avoided, the model shows, and if the 85% had been vaccined, then 178,000 death would have been avoided.

Put another way, the model shows that if 100% vaccination had been reached after peak vaccine rates, 322,324 people in the U.S. would have died from COVID-19 between Jan. 1, 2021, and April 30, 2022, instead of 641,305.

 that 76.3% of the adult population in the U.S. is fully vaccinated and 49.8% have received the first booster.

The researchers also modeled the number of deaths that would have been prevented if all states had reached Maine’s peak rate, the highest in the country, and continued to vaccinate till 100% of the adult population was vaccinated. Under that scenario, which tests an assumption that states would have responded to increased demand for vaccination, the number of vaccine-prevented deaths would have been 338,961.

The researchers noted that their model shows a great deal of state-to-state variability. West Virginia, Wyoming, Tennessee, and Kentucky ranked the lowest when measured by vaccine-preventable deaths per million population — that is, they had the highest number of vaccine preventable deaths on a per million population basis, which is indicative of lower vaccination rates. The model showed District of the Columbia, Massachusetts, Puerto Rico, Vermont and Hawaii had the lowest number of vaccine-preventable deaths on a per million basis.

The dashboard the researchers created allows for other kinds of comparisons. For example, it shows that 29,200 (56%) of Florida’s 52,059 COVID-19 deaths were vaccine preventable (using the 100% scenario compared with 34% (21,730 of 63,877) of California’s.