Prophylactic and therapeutic RSV options amid fluctuating seasonality
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The deviation of many respiratory viral infections from a seasonal cadence is all too real.
Environmental and weather effects have long been attributed to the onset of respiratory illness. Colder climates paired with low humidity promote viral particle stability and transmissibility. Human behavior and physiologic characteristics are also known to impact respiratory virus seasonality. Hand-washing, masking and social distancing have proven to be reliable protective measures. Influenza nearly disappeared during the 2020-2021 season, with a record low number of cases reported. Respiratory syncytial virus activity was slow during the winter months but has mounted an off-season surge corresponding to relaxation of some COVID-19 restrictions. The late surge in RSV cases across the United States prompted clinics and health systems to institute earlier testing practices, medical organizations to reevaluate timing of RSV therapeutic recommendations and pharmacies to supply therapies typically stocked during the late fall to early spring months.
RSV is a single-stranded RNA virus with two surface transmembrane proteins, G and F, which have been shown to play an important role in RSV binding and fusion, respectively. First isolated from chimpanzees in 1956, RSV typically causes self-limiting, coldlike symptoms. The age distribution of RSV disease burden is bimodal, affecting infants and severely immunocompromised and elderly adults. RSV bronchiolitis is one of the leading causes of hospital admission and mortality among infants. By age 2 years, more than 95% of all children in the world are estimated to have been infected with RSV. No curative therapies for RSV infections are available, driving the need for continued optimization of current preventive and treatment efforts.
Prophylaxis
Synagis (palivizumab, Sobi), a humanized monoclonal antibody directed against the conserved F protein, is the only prophylactic therapy for RSV licensed for prevention in pediatric patients at increased risk for severe RSV disease. Infant RSV hospitalization rates are highest between 30 and 90 days after birth, aligning with decreases of transplacental acquired maternal antibodies. Risk factors for severe RSV bronchiolitis include prematurity, cardiopulmonary comorbidities, low birth weight (less than 2.5 g), genetic and chromosomal abnormalities and underlying immunologic disorders. Prematurity poses an increased risk because the period of greatest maternal IgG antibody transfer occurs during the third trimester of pregnancy. In addition, infants are more susceptible to severe RSV infection because of the high surface area-to-volume ratio seen in developing airways and relatively smaller bronchial lumens that are more prone to obstruction.
Palivizumab was approved for use by the FDA in 1998. The American Academy of Pediatrics (AAP) continually revises its recommendations for palivizumab, including a recent update supporting its administration outside of the typical RSV season in response to the shift in the RSV epidemiologic curve.
Presently, the AAP endorses a monthly 15 mg/kg injection for high-risk infants at the beginning and continuing during RSV season for up to five doses, conferring greater protection for roughly 6 months. The IMpact-RSV trial conducted during the 1996-1997 RSV season provided much of the basis for garnering FDA approval. This randomized, placebo-controlled, double-blind trial involved 1,501 infants and young children born preterm (at or before 35 weeks’ gestation), with some who had chronic lung disease of prematurity. The RSV hospitalization rate was 10.6% in the placebo arm and 4.8% among high-risk infants who received palivizumab, yielding a reduction of 5.8% in RSV hospitalizations (P < 0.001). A second randomized, double-blind, placebo-controlled trial conducted from 1998 to 2002 enrolled 1,287 children with hemodynamically significant heart disease. This trial showed a hospitalization rate of 9.7% in the placebo arm and 5.3% among those who received palivizumab.
Despite the costliness of palivizumab, the benefit of reducing hospitalizations is apparent. The delayed RSV surge has forced health systems, pharmacies and clinics to revise their stocking approach. A simple change to stocking practices is easy, although a lot of questions remain unanswered in the setting of COVID-19. Will criteria for use remain the same, or will there be a shift in pediatric patients who are hospitalized with RSV on account of social distancing and lessened day care exposures? Will there be multiple peak seasons, prompting changes to dosing regimens to offer longer protective periods? These are only a few of the questions.
Treatment
Supportive care remains the mainstay of RSV treatment in pediatric and adult patients. Ribavirin is a guanosine analog with activity against a spectrum of RNA viruses, including RSV. Aerosolized ribavirin was approved by the FDA for treatment of RSV in hospitalized infants and young children. The conventional dosing regimen is 6 g delivered over 18 hours through a small particle aerosol generator. An alternative regimen demonstrating noninferiority is 2 g over 3 hours three times daily. Many of the early studies that included pediatric patients were underpowered to draw clear conclusions. Although aerosolized ribavirin may improve subjective outcomes (eg, reduced need for supplemental oxygen) of RSV in pediatric patients, studies supporting its efficacy are limited. The AAP recommends against ribavirin use, although the organization does suggest possible consideration for use in select groups, such as those with complicated congenital heart disease, chronic lung disease, transplant, immunosuppressive disease or patients aged younger than 6 weeks with life-threatening RSV disease. Potential teratogenicity risks to exposed persons, financial constraints and the unpredictable course of RSV necessitate careful evaluation and administration with sound safety measures in place.
RSV treatment strategies in adults vary widely across health systems in the absence of prospective, randomized trials and treatment guidelines. A survey of transplant infectious diseases physicians at 12 Midwest transplant centers found no consensus regarding the use of aerosolized vs. oral ribavirin or IV immunoglobulin administration for RSV treatment in immunocompromised patients. Inconsistency also was seen in dosing regimens among these centers. Most studies using ribavirin in adult RSV infections are retrospective in design, with the majority including hematopoietic stem cell recipients, lung transplants and a small proportion with hematological malignancies.
Several studies show positive trends in earlier use of aerosolized ribavirin yielding reduced lower respiratory tract infection progression and RSV-related mortality. Increasing inhaled ribavirin costs sparked an interest and shift to oral ribavirin therapy use in severely immunosuppressed adults several years ago. Oral ribavirin is less expensive, more readily available and is well tolerated. Dosing strategies vary between weight-based and non-weight-based approaches because some data have been extrapolated from hepatitis C oral ribavirin regimens. Administering oral ribavirin with a high-fat meal has been shown to increase concentrations upwards of 70% considering reductions in absolute bioavailability due to first-pass metabolism. Oral ribavirin distributes into erythrocytes for prolonged periods, which may induce hemolytic anemia, a boxed warning. More robust, prospective data are needed to tease out the most beneficial treatment strategies and patients given a very limited RSV antiviral armamentarium.
RSV continues to circulate in the community, displaying high transmission rates. The once steadfast seasonal nature of RSV is evolving, allowing us to learn more about the multitude and magnitude of factors impacting viral replication and spread. RSV prophylactic and treatment options are few, with palivizumab and ribavirin being beneficial in certain cohorts. Coinciding with other RNA viruses and their capacity to mutate, novel treatments may continue to produce mixed results. A dark vaccine history may turn into a ray of light with more robust protective effects as RSV vaccines under investigation embark on phase 3 trials.
- References:
- Audi A, et al. Front Public Health. 2020;doi:10.3389/fpubh.2020.567184.
- Beaird OE, et al. Transpl Infect Dis. 2016;doi:10.1111/tid.12510.
- Behzadi MA, et al. Front Microbiol. 2019;doi:10.3389/fmicb.2019.01327.
- Committee on Infectious Diseases and Respiratory Guidelines Committee. Pediatrics. 2014;doi:10.1542/peds.2014-1666
- Khawaja F, Chemaly RF. Haematologica. 2019;doi:10.3324/haematol.2018.215152.
- Marcelin JR, et al. Transpl Infect Dis. 2014;doi:10.1111/tid.12194.
- Rebetol [package insert]. Whitehouse Station, NJ: Merck; 1998.
- Turner TL, et al. Clinicoecon Outcomes Res. 2014;doi:10.2147/CEOR.S60710.
- Xing Y, Proesmans M. Eur J Pediatr. 2019;doi:10.1007/s00431-018-03310-7.
- For more information:
- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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