How recent Paxlovid studies explode Covid-19 mortality myths

In December 2021, at the height of the pandemic, the US Food and Drug Administration (FDA) granted emergency use authorization for oral nirmatrelvir-ritonavir (Paxlovid) for outpatient treatment of mild to moderate COVID-19 in adults at high risk of progression to severe disease. In February 2022, a randomized trial of 2,246 unvaccinated adults with COVID-19 reported that starting Paxlovid within 5 days of symptom onset reduced the relative risk of hospitalization or death by 89%, with 13 deaths occurring in the placebo group and none in the intervention group. These results led to expanded access to the drug via pharmacist prescribing and eventually resulted in full FDA approval in May 2023. An American Family Physician article on outpatient COVID-19 management includes clinical recommendations to consider treating high-risk adults with Paxlovid to prevent hospitalization and death.

Does Paxlovid still have value in a population with widespread immunity to COVID-19 from vaccination and prior infection? In a subsequent placebo-controlled trial of the drug with 1,296 patients (one-half vaccinated and with a risk factor for severe disease and one-half unvaccinated with no risk factors) recruited during the Delta and Omicron waves, no significant differences in symptom duration or likelihood of hospitalization or death were found.

Two open-label trials of Paxlovid in the United Kingdom and Canada that collectively enrolled 4,000 participants between April 2022 and September 2024 recently published their findings in a combined paper. Adults older than 50 years and younger adults with high-risk conditions (eg, obesity) were eligible; 98% had received a COVID-19 vaccine. Overall, less than 1% of participants were hospitalized, with no statistical differences between groups, and no one died. Outcomes for immunocompromised patients were similar; in the United Kingdom study, only 3 of 296 were hospitalized, with no benefit of Paxlovid. Although participants in the treatment group appeared to recover several days earlier than did those in the control group, the study’s lack of blinding indicates that symptom improvement may represent a placebo effect rather than a true benefit.

In a related commentary, Dr. Jeremy Faust observed: "The severe event rate (i.e., hospitalizations and deaths) in this paper was so low that it’s difficult to imagine any new antiviral will be able to show such a benefit for the foreseeable future. … So, the next big antiviral against Covid-19 will likely never be shown to prevent deaths or hospitalizations—which … is actually good news."

Why good news? A pernicious myth about the early years of the Covid-19 pandemic is that most people died "with" rather than "from" the infection, even though there were over a million excess deaths in the U.S. and more than 22 million worldwide from 2020-2023 compared to pre-pandemic mortality rates. A related myth is that the older adults who died from Covid-19 would have died from something else soon anyway. A recent analysis of data from the United Kingdom showed that in fact, the "mortality displacement" (death earlier than expected) due to Covid-19 was quite significant: adults over 65 lost a median of 4 to 5 years of life, and two-thirds of women aged 65 to 74 years likely would have survived 5 years or more if they had avoided the infection. The reason for Paxlovid's decreased effectiveness isn't that the drug suddenly stopped working; it's that vaccine and infection-derived immunity have made the very worst outcomes of Covid-19 thankfully uncommon.

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A previous version of this post appeared on the AFP Community Blog.

Screening for testicular cancer is ineffective

In adolescent and young adult males, palpation of the testicles for signs of cancer has traditionally been part of the preparticipation sports physical or well-child examination. Unlike most malignancies that predominantly affect older adults, testicular cancer is most commonly diagnosed between 15 and 34 years of age. Nonetheless, screening for testicular cancer has long been something I have discouraged my students and residents from doing. The rationale is twofold: it's rare, so screening will lead to many false positives and unnecessary evaluations; and more importantly, it's curable even at advanced stages, so earlier detection provides little to no incremental benefit. These were the reasons why in 2011, the U.S. Preventive Services Task Force (USPSTF) reaffirmed its previous recommendation against testicular cancer screening, based on an evidence review that I co-authored that found no new evidence to change this conclusion.

Others have dissented over the years. They argue that young men are among the least likely to visit a doctor and most likely to ignore early symptoms of testicular cancer. American cyclist Lance Armstrong was famously diagnosed with stage 3 testicular cancer at age 24 after ignoring the warning signs for months, having become used to intermittent groin pain and fatigue from grueling hundred-mile training rides up the sides of mountains. (After surgery and chemotherapy, Armstrong not only survived, but went on to win the Tour de France a record seven consecutive times before having his titles rescinded for doping.)

The most salient argument against the USPSTF's "D" recommendation is that until recently, no one had actually studied the outcomes of a sizable real-world program of testicular cancer screening. Consequently, this critique stated, the recommendation grade should be "I" (insufficient evidence). In fact, I have been concerned that the Task Force's 2018 reversal on prostate cancer screening (from "D" to "C" in men age 55 to 69 years) foreshadowed a similar change of heart on testicular cancer the next time they decided to revisit the topic.

A recently published paper appears to have closed the door on that possibility. A team of researchers performed a retrospective cohort study of more than 300,000 Israeli males age 16 to 21 years who had testicular examinations between 2012 and 2021 as part of medical screening evaluations for mandatory military service. All participants were followed for the duration of their service (generally 3 years). 43 testicular cancers developed during the study (incidence rate of 3.67 per 100,000 person-years); even though the vast majority were diagnosed clinically rather than through screening, 86% were stage 1. Of the 6 cancers determined to have been present at the initial exam (diagnosed within 6 months), screening detected 4 at the cost of 804 false positives. More than 75,000 screening exams, 176 ultrasound scans, and 112 urologist visits were required to detect a single cancer. The researchers concluded that "the low sensitivity, high number needed to screen, frequent unnecessary evaluations, and low incidence of testicular cancer suggest that routine screening of asymptomatic adolescents is ineffective."

Lancaster Medical Heritage Museum's Object of the Month: The Pill Roller

I serve on the Board of Directors of the Lancaster Medical Heritage Museum, and we have inaugurated an "Object of the Month" feature to highlight interesting items from the museum's collections. Here is the one for May.

Before modern pharmacies and mass-produced medications, medicines were often made by hand.

Invented around 1750 in Germany, the pill roller was a staple of apothecaries for over two centuries. At a time when prescriptions were custom-prepared, tools like this ensured that each pill was measured, shaped, and cut with care and consistency.

Using a wooden board with grooved brass channels and a hand-held roller, pharmacists would:

• Grind ingredients into a powder
• Mix them with a binding agent to form a paste
• Roll the mixture into a cylinder
• Lay it across the board and slice it into evenly sized pills

Each dose was then counted and bottled, ready for the patient.

Though largely replaced by commercial pill-making machines in the late 19th century, pill rollers remained in use into the 1930s, bridging the gap between traditional apothecary practices and modern pharmaceutical production.

We’re fortunate to have two pill rollers on display in our Pharmacy exhibit, offering a glimpse into a time when medicine was as much a craft as it was a science.

Does a prescription to drink more fluids prevent recurrent kidney stones?

Adults who have had one or more kidney stones are typically advised to increase fluid intake. The supporting evidence for this preventive intervention is limited, however. A 2014 Agency for Healthcare Research and Quality Effective Health Care review identified low-quality evidence from two small randomized trials of people with calcium stones. In these trials, increasing fluid intake to maintain a urine output of more than 2 liters (L) per day over 3 to 5 years reduced the relative risk of symptomatic or radiographic stone recurrence by 45%, with a number needed to treat of 7. No adverse effects were observed. As a result, the American College of Physicians recommended in a clinical practice guideline that people with kidney stones and a daily urine output of less than 2 L increase their fluid intake if not contraindicated for other reasons.

Similarly, Drs. Leonardo Ferreira Fontenelle and Thiago Dias Sarti wrote in a 2019 American Family Physician review article that “the most important lifestyle modification to prevent recurrent kidney stones is to increase fluid intake to 2.5 to 3 L per day to guarantee diuresis of 2 to 2.5 L per day and a urine specific gravity lower than 1.010.”

A trial published in March, the Prevention of Urinary Stones with Hydration (PUSH) study, tested a 2-year multicomponent behavioral intervention to increase fluid intake in 1,658 participants 12 years and older with previous kidney stones from six medical centers in six different US states. The intervention comprised (1) a prescription to increase urine volume to more than 2.5 L per day, (2) a financial incentive of $1.50 per day for the first 6 months for adhering to the fluid prescription (verified by a Bluetooth-enabled smart water bottle), and (3) health coaching and automated text messaging reminders to overcome barriers to adherence. Control participants were also provided a smart water bottle but were not required to use it. The primary outcome was symptomatic stone recurrence.

By the end of the study, a statistically similar percentage of the intervention (19%) and control (20%) groups had either passed a kidney stone or undergone a procedural intervention for a stone. This nondifference occurred despite increased fluid intake in the intervention group; daily average urine volume peaked at 1.8 L at 6 months and gradually declined to less than 1.6 L by 24 months. At 6 and 12 months, intervention participants were more likely to report urinary frequency, urgency, and nocturia. More intervention participants developed asymptomatic hyponatremia (12 vs 2 in the control group; p = 0.018); no one developed hyponatremia requiring hospitalization.

Although the failure of the intervention to achieve the daily urine volume goal likely contributed to the PUSH study’s negative result, it is hard to imagine a different primary care–feasible intervention performing any better. Further, the increases in urinary symptoms and hyponatremia associated with the intervention provided evidence of rare but clinically significant harms. An accompanying editorial reasonably suggested, “If adherence to foundational advice is unattainable even under optimal trial conditions, then … framing [fluid intake] targets more flexibly with individualized goals that are aligned with work or study patterns, beliefs, access to palatable water, thirst cues, and other competing demands might be more successful.”

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This post first appeared on the AFP Community Blog.

Saving AHRQ and the USPSTF

AcademyHealth CEO Aaron Carroll, MD recently submitted testimony to the House Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies about the dire condition of the Agency for Healthcare Research and Quality (AHRQ), where I spent 4 years as a medical officer early in my career. Dr. Carroll points out the immense return on investment that AHRQ has provided over the years - for example, saving $7.7 billion in U.S. health care costs by reducing hospital-acquired infections from 2014 to 2017 on a budget of around $300 million per year - and its unique, irreplaceable function among federal health agencies:

NIH [National Institutes of Health] studies diseases. AHRQ studies how health care is delivered. These are different missions. NIH can tell us that a treatment works in a clinical trial. AHRQ tells us whether that treatment reaches patients in a rural hospital, whether it is implemented safely, what it costs, and whether a critical access hospital in a rural county can actually use it. No other federal agency performs this function. Eliminating AHRQ does not transfer these capabilities elsewhere. It simply ends them. 

Notably, Congress rejected HHS Secretary Robert F. Kennedy Jr.'s 2025 proposal to eliminate AHRQ. But Dr. Carroll observes that the Trump administration has effectively carried out this plan anyway, by laying off most of the agency's staff and the entire grants management division, crippling its ability to function as a funder of health services research:

AHRQ has not awarded a single new grant since April 2025. An estimated $80 million in FY25 appropriated research funding was allowed to expire unused—a pattern consistent with the Government Accountability Office’s ongoing impoundment investigation. In FY26, the agency has not funded any of the noncompetitive continuing grants it is statutorily obligated to pay. The FY27 congressional justification now explicitly states a policy of “no new grants,” ending AHRQ’s four-decade role as the nation’s primary funder of health services research—a decision Congress never authorized.  

Similarly, former New York City and Philadelphia Health Commissioner Thomas Farley, MD wrote today on his Substack that the U.S. Preventive Services Task Force is being "quietly strangl[ed]" by being deprived of AHRQ support staff, not being convened since March 2025, and not appointing replacements for 5 members whose terms expired on December 31. He cites the recent ACC/AHA dyslipidemia guidelines as an example of what fills the preventive care vacuum when the USPSTF (which wrote its own cholesterol guideline in 2022) is effectively silenced:

Are cholesterol tests for kids and coronary artery scans for adults now scientifically justified? Here’s the problem: I do not know. It takes more expertise and time than I have to sift through all the many complicated studies to figure that out. ... But I do know that (by my count) 12 of the 33 members of the writing committee and 17 of the 29 members of the review committee for the ACC/AHA guidelines have financial ties to biotech companies that are likely to make money from this testing and treatment. (None of the USPSTF members have these conflicts.) And I know this rule: if you’re wondering whether you need a new pair of shoes, don’t ask a shoe salesman.

The muddle about cholesterol testing, statin treatment and coronary artery scans is just one example of what we are losing from the USPSTF’s paralysis. ... Thanks to Kennedy, dozens of other important questions on the USPTF consideration list are also languishing. Each month that the Task Force is in deep freeze our ignorance accumulates. ... Surely we can afford to have a group of experts who are not motivated by profit guiding us on which medical services actually keep us healthy. With the USPSTF dead in the water, the war on science begins to feel like a war on us.

Nearly a year ago, I wrote a Medscape commentary that appealed to readers to "Save the USPSTF." The USPSTF still needs saving. So does AHRQ. So does the entire taxpayer-funded scientific apparatus at HHS devoted to keeping people healthy that RFK Jr. has wrecked.

AI health tools for the general public fall short

A 2025 American Family Physician editorial by Dr. Joel Selanikio discussed how artificial intelligence (AI) tools had accelerated an existing trend of “patients bypassing physicians to diagnose and treat themselves,” which began with over-the-counter drugs and online search engines. This direct-to-consumer health care approach received a boost in January with OpenAI’s launch of ChatGPT Health, which invites users to upload their medical records and health data from apps for personalized recommendations.

AI chatbots can provide helpful responses to health questions in several low-stakes contexts, as outlined in this handout from Dewey Labs: translating medical jargon, brainstorming possible causes of symptoms, summarizing research or test results, and preparing questions for an upcoming doctor’s visit. However, a recent study in Nature Medicine highlighted ChatGPT Health’s significant limitations in triaging patients with acute problems to appropriate levels of care.

Dr. Ashwin Ramaswamy and colleagues compared the chatbot’s responses to “60 clinician-authored vignettes across 21 clinical domains under 16 factorial conditions (960 total responses)” to triage levels assigned independently by three physicians: non-urgent, semi-urgent, urgent, and emergency. ChatGPT Health performed well in triaging semi-urgent and urgent clinical situations, but it over-triaged 65% of non-urgent situations and under-triaged 52% of true emergencies. For example, it recommended evaluation in 24 to 48 hours for patients with diabetic ketoacidosis and impending respiratory failure rather than sending them directly to the emergency department. Just as concerning, patients with suicidal ideation were less likely to receive crisis interventions when they had identified a method of self-harm than when they had no identified method:

The crisis guardrail finding may be the most consequential failure mode exhibited in the entire study. … A guardrail that fires for ‘haven’t thought through how I would do it’ but not for ‘thought about taking a lot of pills’ is not calibrated to clinical risk and users have no basis to anticipate when it will or will not fire. The capability to recognize mental health crises and connect users with crisis resources is a basic prerequisite for any consumer health platform. Our data show this prerequisite has not been reliably met.

In another study, three AI chatbots were provided with 10 detailed medical scenarios and tested on their ability to diagnose the condition and recommend appropriate management. In the United Kingdom, 1,298 adults were provided the scenarios and randomized to use one of the chatbots or a usual source of their choice (typically an online search engine). When researchers input the full scenarios, the chatbots diagnosed 95% of the conditions and correctly managed them 56% of the time. However, when intervention participants shared elements of the scenarios in live conversations, the chatbots performed much worse, correctly diagnosing 34% of the time and recommending appropriate management in 44%; this result is no better than control participants using a search engine. Researchers observed that participants often failed to provide enough information to make the diagnosis, and slight changes in symptom emphasis or wording of questions frequently led to dramatic differences in advice.

Bottom line: For patient-facing chatbots such as ChatGPT Health to diagnose and triage problems appropriately and safely, it isn’t enough to passively process the incomplete clinical data they are provided. They will need to get much better at asking the right questions to elicit information that patients may not be aware is relevant.

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This post first appeared on the AFP Community Blog.