A COVID-19 treatment was followed up more than a year later—not just for survival, but for lingering harm. In this small extension study, most measured long-term findings were reassuring, but the evidence has important limits. The SARS-CoV-2 pandemic had resulted in more than six hundred fifteen million infections and six point five million deaths by October 2, 2022, at significant costs to healthcare systems and societies worldwide.

The focus initially fell on the acute burden of COVID-19, but SARS-CoV-2 infection can also provoke longer-term mental and physical health consequences. Persistent symptoms such as fatigue, dyspnea, chest pain, cognitive disturbances, or arthralgia three months after infection are referred to as post-COVID-19 disease, or long COVID.

Between ten and twenty-five percent of patients will experience long COVID, which can limit daily activities, increase long-term sick leave, and produce sequelae lasting more than one year. The APLICOV-PC proof-of-concept study assessed the safety and preliminary efficacy of three plitidepsin dose levels—one point five, two point zero, and two point five milligrams—administered for three consecutive days in hospitalized adults with COVID-19.

The trial met its primary endpoint of safety and feasibility for the three plitidepsin doses administered. Results suggested that plitidepsin was associated with a mean three point two five log ten reduction in baseline viral load by day fifteen.

By day fifteen, eighty-two percent of patients had been discharged, while the study also reported relevant effects on lymphocyte reconstitution and other inflammatory parameters. The E-APLICOV study was designed to evaluate whether plitidepsin treatment in patients hospitalized for COVID-19 could have a relevant impact on the emergence of long-term sequelae resulting from SARS-CoV-2 infection.

So the follow-up question was not only whether patients recovered from the hospitalization, but whether long-term sequelae emerged after treatment. The main objective was to evaluate the incidence of post-COVID-19 morbidity and characterize the profile of complications in patients who had participated in APLICOV-PC.

The study assessed post-COVID-19 complications after exposure to plitidepsin at flat doses of one point five, two point zero, and two point five milligrams per day, for three consecutive days as a ninety-minute intravenous infusion. Of the forty-five adults who received plitidepsin in APLICOV-PC, thirty-four were enrolled in the extension.

Among those included, five patients had mild COVID-19, nineteen had moderate COVID-19, and ten had severe COVID-19 at the time of plitidepsin treatment, using FDA criteria. A median of sixteen point eight months had elapsed from the first plitidepsin dose to the start of the extension, with a range of fifteen point two to nineteen point five months.

Most patients were male and Caucasian: twenty-three patients, or sixty-seven point six percent, in each category. Figure one traces participant selection for the E-APLICOV extension. It starts with forty-five patients from the APLICOV-PC study, then lists exclusions: five patients whose sites could not reach them, three with distant home locations, and three COVID-nineteen-related deaths during APLICOV-PC.

The resulting analysis included thirty-four patients, defining the study population used to assess post-COVID-nineteen morbidity after plitidepsin exposure. Table one summarizes baseline characteristics for the thirty-four E-APLICOV patients across the one-point-five, two-point-zero, and two-point-five milligram groups.

The overall median age was fifty-three years, median body mass index was twenty-nine-point-seven kilograms per square meter, and sixteen patients had two or more comorbidities. Most patients had moderate COVID-19, thirty-three were vaccinated, and thirty-one were seropositive for SARS-CoV-2, providing important context for interpreting outcomes in this extension study.

Nearly fifteen percent of patients—five people—were diagnosed with COVID-19 after the APLICOV-PC study was completed, approximately thirteen to fifteen months after the last patient was included in APLICOV-PC. The study found several grade two disease-related complications in one patient each, or two point nine percent: alopecia, cough, diabetic metabolic decompensation, hyperglycemia, and interstitial lung disease.

Grade two asthenia was described in two patients, or five point nine percent. There were no clinically relevant abnormalities in hematological parameters, and none of the patients experienced a thromboembolic event.

Table two summarizes post-COVID-19 complications related to the study disease, reporting each patient’s worst CTCAE version five grade. Most recorded events are grade one, while grade two entries include asthenia, alopecia, cough, diabetic metabolic decompensation, hyperglycemia, and interstitial lung disease.

Asthenia was reported in thirteen patients overall, or thirty-eight point two percent, and the table also records attention deficit, general malaise, and tingling in extremity in five patients each, or fourteen point seven percent. At study entry, spirometry was normal in twenty-nine patients, or eighty-five point three percent, and lung-diffusion tests were normal in twenty-seven patients, or seventy-nine point four percent.

Before the six-minute walk test, every patient scored zero to two on the Borg scale, corresponding to no or slight dyspnea. After the test, twenty-four patients, or seventy point six percent, still scored zero to two; six patients had moderate dyspnea scores, and four had severe dyspnea.

Only two patients stopped or paused during the test, and none experienced symptoms at the end of the exercise. Table 3 summarizes pulmonary function by plitidepsin dose, using spirometry, the mMRC dyspnea scale, and lung-diffusion testing. Overall, spirometry was normal for FVC in 32 patients, or 94.1 percent, and for FEV1 in 29, or 85.3 percent; the FEV1/FVC ratio was normal in 29, or 85.3 percent.

DLCO was normal in 27 patients, or 79.4 percent, while mMRC scores were most commonly zero, reported for 21 patients, or 61.8 percent. The study summary points to the absence of CTCAE version five grade three to four complications and clinically significant EKG abnormalities.

It also points to the low rate of disease-related complications, chest X-ray findings, and requirements for oxygen supplementation in the included patients. On that basis, plitidepsin demonstrated long-term safety in adults hospitalized for COVID-19.

However, the study had a low sample size and lacked a control group in APLICOV-PC, so its complication rate should be interpreted cautiously rather than as proof of prevention. Among 34 followed patients, the study found no severe CTCAE complications or thromboembolic events, and most pulmonary tests were normal.

But the small sample and lack of a control group mean this is a safety signal, not proof that plitidepsin prevents long COVID.