Hydroxychloroquine has been a highly controversial potential treatment for COVID-19. To date, available evidence has consisted of in vitro data as well as some heavily flawed studies from France. A new pre-print from China offers the most meaningful investigation of hydroxychloroquine to date.
Tang et al. is a multi-center, open-label RCT involving administration of hydroxychloroquine to 150 patients hospitalized with COVID-19. Sixteen government-designated COVID-19 treatment centers were involved. The dose of hydroxychloroquine used was 1,200 mg daily for three days, followed by 800 mg daily for 2-3 weeks. This is a huge dose of hydroxychloroquine (in comparison, the most commonly used regimen in the United States currently seems to be 800 mg on the first day followed by 400 mg daily for four days). Patients with severe renal or hepatic disease were excluded, to avoid potential drug accumulation.
Patients were fairly well-matched at baseline. Most patients had relatively mild disease (e.g., with a low rate of dyspnea or hypoxemia). Treatment was initiated late, an average of 16-17 days after disease onset:
Laboratory studies were likewise well matched. Again, patients appear to have had mild disease (with fairly high absolute lymphocyte counts and low levels of C-reactive protein).
The primary endpoint was viral clearance by 28 days. There was no difference in this endpoint, or in viral conversion at a variety of intermediary time-points.
This isn't a patient-centered endpoint, but it is an extremely important endpoint nonetheless. This endpoint most directly addresses the question: does hydroxychloroquine exert anti-viral activity in vivo? The answer seems to be: nope. Even if the drug were administered too late to affect the clinical course of the infection, if it exerted any anti-viral activity then we might expect to see that effect here. If anything, there might be a trend towards delayed viral clearance in patients treated with hydroxychloroquine.
One secondary endpoint was the rate of improvement in symptoms over one month (defined as defervescence, improved oxygen saturation, and disappearance of respiratory symptoms). There was no significant difference in this endpoint:
A retrospective, adjusted analysis did find some improvement in symptoms. However, the validity of an adjusted analysis in a secondary endpoint is dubious.
Numerous lab values were tracked among patients (e.g., C-reactive protein, erythrocyte sedimentation rate, interleukin-6, tumor necrosis factor-alpha). Hydroxychloroquine didn't affect most of these parameters. There was a small difference in C-reactive protein levels, of unclear clinical or statistical significance (p=0.045 in the context of multiple comparisons).
Adverse events were found in 30% of patients treated with hydroxychloroquine, versus 9% of the control group. Although not statistically significant, progression to severe disease occurred at a higher rate in patients receiving hydroxychloroquine.
The study has major limitations, for example:
- Lack of blinding or placebo control.
- Performance of the study by a contract research organization, rather than directly by the investigators.
- Early termination due to recruitment problems and the impression of benefit (which may have led to under-powering).
- Relatively long delay between symptom onset and treatment initiation (16-17 days).
Nonetheless, this study currently represents the highest available quality of evidence regarding hydroxychloroquine.
timing of antiviral therapies
This is now the third anti-viral therapy to disappoint us within a few weeks (preliminary data on lopinavir/ritonavir and remdesivir were both unimpressive). This raises a question of whether any anti-viral therapies will be beneficial. Especially among the critically ill, patients often present relatively late (at a time-point when viral load is already falling anyway). Much of the pathogenesis of critical illness seems to result from dysregulated inflammation, rather than direct viral cytopathic effect. This raises a question of whether any antiviral treatment will be beneficial for late-presenting patients with severe illness.
Of course, it is possible that earlier use of hydroxychloroquine could be beneficial (e.g., perhaps at the first signs of illness on an out-patient basis). This is under investigation and additional data is likely to be forthcoming soon. Even if this does work in the outpatient clinic, it would probably have little impact on the management of these patients within the intensive care unit.
- This is the first multi-center RCT investigating the use of hydroxychloroquine for COVID-19. 150 adult patients hospitalized with COVID-19 were randomized in an open-label, non-blinded fashion.
- Hydroxychloroquine had no effect on the duration of viral detection (despite the use of high doses and a prolonged 2-3 week course).
- Clinically, there was no discernible beneficial effect from hydroxychloroquine. However, hydroxychloroquine did appear to cause some side-effects (most notably diarrhea).
- Further studies on hydroxychloroquine will likely be emerging soon. For now, the best available evidence does not support the use of hydroxychloroquine in COVID-19. Given evidence of harm without evidence of benefit, it seems prudent to restrict the use of hydroxychloroquine to randomized controlled studies for the time being.