Immunization and immunotherapy updates for family physicians

 - Kenny Lin, MD, MPH

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) 2021 Adult and Child/Adolescent Immunization Schedules included a number of key updates that are discussed in the February 15 issue of AFP. The schedules included information on the two messenger RNA vaccines against SARS-CoV-2 that have received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA): the Pfizer-BioNTech vaccine for persons older than 16 years and the Moderna vaccine for persons older than 18 years. As Dr. Jennifer Middleton noted in a previous blog post, additional vaccines with different mechanisms may become available in the U.S. soon; data on the Janssen adenovirus vector vaccine will be reviewed at a meeting of the FDA's Vaccines and Related Biological Products Advisory Committee later this week.

The ACIP recommends shared decision-making (SDM) for the 13-valent pneumococcal conjugate vaccine (PCV13) in adults older than 65 years, meningococcal B vaccination for adolescents and young adults aged 16–23 years, hepatitis B vaccination for adults older than 60 years with diabetes mellitus, and human papillomavirus vaccination for adults aged 27–45 years. According to its website, "Generally, ACIP makes shared clinical decision-making recommendations when individuals may benefit from vaccination, but broad vaccination of people in that group is unlikely to have population-level impacts." In a study published in the Journal of General Internal Medicine, researchers surveyed 617 primary care physicians recruited from the American College of Physicians and the American Academy of Family Physicians about their knowledge, attitudes, and experience with SDM vaccine recommendations. Most participants agreed that SDM requires more time than typical vaccine recommendations, is facilitated by specific talking points, can create confusion for patients, and may be difficult to implement. Compared to family physicians, general internists were more likely to report not knowing how to implement SDM recommendations as intended by the ACIP.

The February 1 issue of AFP included an article on targeted cancer therapies by Drs. Claire Smith and Vinayak Prasad. Targeted therapies may be monoclonal antibodies, small molecule inhibitors, antibody-drug conjugates, and/or immunotherapy. Immune checkpoint inhibitors (ICIs) - monoclonal antibodies that block inhibitory regulatory proteins and lead to T-cell activation - have a wide range of toxic effects on various organ systems, with thyroiditis being the most common. Family physicians should be aware of these potential adverse effects and their initial management in patients being treated with ICIs.

Finally, the AFP article mentioned the increasing financial toxicity of targeted cancer therapy:

In 2020, the average out-of-pocket cost to a patient for a course of oral cancer therapy was estimated at $5,663. According to one large analysis, 20% of patients with cancer take less medication than prescribed, 19% partially fill oral cancer therapy prescriptions, and 24% avoid filling a prescription at all. Many patients in this study reported spending less money on food, leisure, and clothing. Approximately 2% of patients will declare bankruptcy during their treatment; those with advanced disease are more likely to declare bankruptcy. Bankruptcy during cancer treatment increases the risk of death.

In a recent commentary in JAMA Internal Medicine, Dr. Prasad argued that the problem of unaffordability is compounded by the FDA's lenient approval process for new cancer drugs and subsequent mandatory Medicare coverage for approved drugs without price negotiation. Only a fraction of cancer drugs approved in the U.S. (often based on studies with surrogate end points rather than evidence of benefits in survival or quality of life) are approved for broad coverage in England and Canada. Not only is the clinical effectiveness of many of these drugs uncertain, but their value (cost-effectiveness) is questionable as well.

New(old) treatments for COVID: inhaled budesonide & the -umabs

 - Jennifer Middleton, MD, MPH

Although the Biden administration appears to be on track to meet its goal of 100 million COVID vaccines given in its first 100 days, the United States (US) is still unlikely to get most adults fully vaccinated before early 2022. With nearly 97,000 persons a day diagnosed with COVID-19 in the US last week, the need for effective COVID-19 treatment measures isn't going away any time soon. Researchers have identified two classes of medications that may benefit patients with symptomatic COVID-19, both well-known medications already in use for other conditions.

A small trial in the United Kingdom (UK) randomized 146 persons with mild COVID-19 to receive either inhaled budesonide (Pulmicort) or "usual care;" as with many COVID studies, this study's results have been publicized prior to full peer review and publication. The researchers used a composite end point of urgent care visit, emergency department visit, or hospitalization and found a number needed to treat of 8 to prevent 1 of those events. The small size of this trial may make it tempting to dismiss its findings, but as inhaled budesonide is generally well-tolerated and is relatively inexpensive, it still may be reasonable to use. Several other larger trials are currently underway evaluating inhaled budesonide, including the PRINICIPLE trial in the UK. 

Persons with more severe COVID-19 may benefit from tocilizumab or sarilumab, interleukin-6 receptor antagonists currently used for persons with rheumatoid arthritis. Last week, the UK's National Health Service informed its physicians that a trial randomizing 800 participants in intensive care for COVID which compared these two medications to usual care found that "[h]ospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for [the] control [group]." Smaller trials had been less promising for this class of medications, though these studies were conducted earlier in the pandemic:

More studies will be needed to clarify when, and in which patients, tocilizumab and sarilumab work best, and to untangle why their benefits cropped up clearly in some studies, but not others.... It’s also challenging to compare studies coming out now to earlier trials that were conducted when the virus was much less understood, treatments were doled out with less know-how and mortality rates were even higher.

It remains to be seen whether the US Food and Drug Administration (FDA) and/or the Centers for Disease Control and Prevention (CDC) will follow the UK's lead and formally recommend these treatments for COVID-19, though it's heartening that research efforts continue to identify ways to lessen its burden. The AFP By Topic on Coronavirus Disease 2019 (COVID-19) has a section on "Treatment" which includes this Rapid Evidence Review of Outpatient Management of COVID-19 if you'd like to read more. 

Are primary care physicians overdiagnosing cutaneous melanoma?

 - Kenny Lin, MD, MPH

In an editorial in the February 1 issue of AFP, Dr. Jenny Doust and colleagues wrote about the problem of widening disease definitions, a common phenomenon in which the definition of a disease is "broadened over time to include milder and earlier cases," leading to harm "by exposing more patients to the adverse effects of treatments, triggering investigation and prescribing cascades, increasing anxiety, and placing a financial burden on patients and the wider society." Expanding the number of patients diagnosed with disease increases the burden on primary care physicians called on to manage these additional cases, even when it is uncertain if earlier interventions prevent morbidity or mortality. Illustrative examples of wider disease definitions include hypertension, polycystic ovary syndrome, breast cancer, and autism. What can family physicians do about it? The authors responded:

Recognizing the problem is the first step in tackling it. In particular, family physicians should not blindly accept new definitions and testing guidelines without an adequate understanding of the harms and benefits of the changes and the implications for our patients and wider practice.

Along similar lines, a recent analysis in the New England Journal of Medicine by Dr. H. Gilbert Welch and colleagues examined the drivers of the dramatically increased incidence of cutaneous melanoma in the U.S., which today is 6 times as high as in 1975 despite essentially no change in melanoma mortality. They pointed out that exposure to ultraviolent (UV) radiation (including tanning bed use) cannot account for more than a small portion of this increase. Instead, they argued that increased diagnostic scrutiny - "the combined effect of more screening skin examinations, falling clinical thresholds to biopsy pigmented lesions, and falling pathological thresholds to label the morphologic changes as cancer" - is most likely to be responsible for the epidemic of new diagnoses. Not only has the annual percentage of fee-for-service Medicare beneficiaries undergoing skin biopsies nearly doubled since 2004, but pathologists frequently upgraded skin biopsy specimens obtained in the late 1980s from benign to malignant when evaluating the same specimen two decades later. Primary care physicians contribute to widening the definition of cutaneous melanoma by performing or referring for biopsy small (<6 mm), incidentally detected skin lesions and screening patients with dermoscopy, which identifies more melanomas than visual inspection alone but is not well studied in primary care settings.

The U.S. Preventive Services Task Force (USPSTF) has concluded that current evidence is insufficient to assess the balance of benefits and harms of skin cancer screening in asymptomatic adults. Nonetheless, more than half of family physicians and general internists in a 2011 survey reported performing full-body skin examinations for skin cancer screening. In a 2020 AFP editorial, Drs. Michael Pignone and Adewole Adamson (Dr. Adamson also co-authored the NEJM analysis) observed that "compared with usual care, potential effects of screening on morbidity and mortality from keratinocyte carcinoma are at most small, and screening cannot be justified based on the impact on keratinocyte carcinoma alone." Dr. Welch and colleagues went one step further, arguing that the established harms of skin cancer screening already outweigh any potential benefits:

The increase in melanoma diagnoses by a factor of 6, with at least an order of magnitude more persons undergoing a biopsy and no apparent effect on mortality, is more than enough to recommend against population-wide screening. ... It [screening] has been effectively promoted under the guise of public health, with the combination of frightening messages about skin cancer and the premise that screening can only help. However, medical care should be driven by patient needs, not system needs. Now is not the time to add more anxiety and expense to an already anxious and expensive world.

Not surprisingly, dermatologists have a more positive view of skin cancer screening, as reported in a news story about the analysis by Dr. Welch and colleagues that quoted the president of the American Academy of Dermatology as stating that "an aggressive approach to prevention and treatment is entirely appropriate for a disease that kills 20 Americans each day." Of course, no one is urging clinicians to stop counseling patients on minimizing their exposure to UV radiation; indeed, the USPSTF recommends behavioral counseling to prevent skin cancer, particularly for children, their parents, and young adults. But screening for skin cancer, which has effectively widened the definition of cutaneous melanoma and driven widespread overdiagnosis - is a different story. To give Dr. Doust and colleagues the last word: "We [primary care physicians] are not here to passively enact specialist recommendations. Instead, we need to more assertively act as advocates for our patients and our communities."

COVID vaccine update: new data & new vaccines

 - Jennifer Middleton, MD, MPH

As challenges with distributing COVID-19 vaccines continue, additional data is emerging regarding the two mRNA vaccines already being given in the United States (US) along with Johnson & Johnson's Janssen vaccine and the Novavax vaccine. The Janssen and Novavax vaccines are likely to soon apply for Emergency Use Authorization.

Preliminary data out of Israel suggests that the Pfizer/BioNTech vaccine is even more effective than phase 3 trials in the US suggested. The Israeli Health Ministry announced last week "that of 428,000 Israelis who had received their second doses, only 63, or 0.014 percent, had contracted the virus." It's important to note that this data hasn't yet been subject to peer review or published, though the health fund gathering the data reportedly plans to do so very soon.

Johnson & Johnson also shared preliminary data from its Janssen vaccine international phase 3 trial last week. The Janssen vaccine uses an adenovirus vector to deliver the SARS-CoV-2 spike protein. They enrolled over 43,000 participants from the US, Latin America, and South Africa and found that:

Among all participants from different geographies and including those infected with an emerging viral variant, Janssen’s COVID-19 vaccine candidate was 66% effective overall in preventing moderate to severe COVID-19, 28 days after vaccination. The onset of protection was observed as early as day 14. 

Although these numbers are not as impressive as the Pfizer/BioNTech and NIH/Moderna vaccines, they still represent acceptable efficacy. Perhaps more importantly, the vaccine demonstrated "complete protection against COVID-related hospitalization and death," with none of the vaccinated participants experiencing hospitalization or death 28 days or more after vaccination. With the added bonuses of only requiring one vaccination and much simpler storage requirements (regular refrigeration), the Janssen vaccine may be an important addition to the COVID-19 pandemic arsenal. 

Lastly, the Novavax vaccine (NVX-CoV2373), which works via engineered spike proteins, is showing reasonable efficacy in trials in the United Kingdom (UK). Over 15,000 participants received the 2 doses of the Novavax vaccine in the UK:

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

"The newer, more contagious variant first identified in Britain was found to have caused about 50 percent of the cases in the trial, Novavax said." Phase 2b trials in South Africa have been less impressive, with only 60% efficacy (though with a very wide 95% confidence interval of 19.9-80.1), likely due to the South Africa SARA-CoV-2 variant. Novavax is already at work on another vaccine targeting this variant. Similar to the Janssen vaccine, the Novavax vaccine can be stored in a regular refrigerator. 

Assuming supply and distribution challenges are eventually overcome, vaccine hesitancy may pose another threat to decreasing SARS-CoV-2 transmission, which is critical to slowing the development of additional COVID variants. The Centers for Disease Control and Prevention (CDC) has resources and talking points to support clinicians with these conversations, and the AFP By Topic on Coronavirus Disease 2019 (COVID-19) also includes this article on "Helping Patients Make Healthy Decisions on COVID-19."