Choosing the Right COVID Prophylaxis

Last month, we introduced Maryam, a 31-year-old woman with acute COVID. We discussed the limited efficacy of antiviral medications to help younger, healthy patients with COVID, but Maryam was concerned regarding the safety of her 88-year-old grandmother, who lives with her in a small apartment.Maryam provides more information before she leaves the clinic. Her grandmother has an extensive past medical history that includes type 2 diabetes, hypertension, congestive heart failure with reduced ejection fraction (HFrEF), peripheral vascular disease, and mild cognitive impairment. She currently has no upper respiratory symptoms, but Maryam laments how much her grandmother has “slowed down” in the past year.Recommending N95 masks is viable, but I would most prefer the initiation of postexposure prophylaxis (PEP) with ensitrelvir. Maryam’s grandmother has multiple risk factors for complications of COVID, including her age, type 2 diabetes, and HFrEF. I would want her maximally protected against infection.Ensitrelvir is a 3CL protease inhibitor, which means it acts on a key factor for replication of the SARS-CoV-2 virus. It has been approved for the treatment of active COVID in Japan and Singapore, and it was approved for postexposure prophylaxis in the US for household contacts of persons with COVID in June 2026.A randomized, placebo-controlled trial including over 2000 asymptomatic individuals with household exposure to COVID found good efficacy for ensitrelvir as PEP. The mean age of the study cohort was 42 years, and 98% of participants had evidence of prior immunity against SARS-CoV-2.The risk ratio for lab-confirmed COVID with at least one symptom was 0.33 (95% CI, 0.22-0.49) for ensitrelvir vs placebo. There was little heterogeneity in the efficacy of ensitrelvir when comparing patient subgroups, including older adults and adults at high risk for complications of COVID. Finally, symptom scores early in infection were lower in the ensitrelvir group vs the placebo group among participants who developed COVID.The rate of adverse events was 15% for both the ensitrelvir and placebo groups. There were no serious adverse events associated with any study treatment.Of note, ensitrelvir has also been demonstrated to have modest efficacy for acute infection with COVID, with improvement in symptoms advanced by about 1 day faster vs placebo when treatment is initiated within 3 days of symptom onset. However, ensitrelvir does not have this indication for acute treatment in the US.Nirmatrelvir-ritonavir was studied as PEP among household contacts of persons with COVID as well. Rates of household transmission were low overall in this study, and nirmatrelvir-ritonavir did not reduce the risk for transmission vs placebo. Pemivibart is FDA-approved as preexposure prophylaxis (PrEP) against COVID. It should not be used as a means to prevent COVID among individuals recently exposed to the virus. Pemivibart was approved as PrEP in a placebo-controlled study using the immune response to two intravenous doses of pemivibart as the primary outcome.Pemivibart met criteria as protective against the JN.1 variant of SARS-CoV-2 based on participants’ immune response. Moreover, a sustained reduction in the incidence of clinical COVID was observed in the pemivibart vs placebo cohorts through 12 months (relative risk reduction, 73.9%).However, 2%-3% of participants receiving pemivibart experienced an infusion reaction, including anaphylaxis in 0.6% of these participants. Pemivibart should be reserved for patients over 12 years of age with moderate-to-severe immunosuppression.COVID will not disappear, and it still resulted in approximately 1000 hospitalizations per week in the US in May 2026. Having effective means for prophylaxis can help our highest-risk patients avoid the worst outcomes of COVID. However, most patients will not know about these options. It is up to us as healthcare professionals to educate patients about COVID prevention and prescribe and protect vulnerable individuals. As always, please provide your comments. I can address them during the next edition of Sound Off! And thank you, as always, for participating in this activity!