Hydroxychloroquine (HC) ± azithromycin (AZ) is widely used for Covid-19. The Qatar Prospective RCT of Expediting Coronavirus Tapering (Q-PROTECT) aimed to assess virologic cure rates of HC±AZ in cases of low-acuity Covid-19.
Methods
Q-PROTECT employed a prospective, placebo-controlled design with blinded randomization to three parallel arms: placebo, oral HC (600 mg daily for one week), or oral HC plus oral AZ (500 mg day one, 250 mg daily on days two through five). At enrollment, non-hospitalized participants had mild or no symptoms and were within a day of Covid-19 positivity by polymerase chain reaction (PCR). After six days, intent-to-treat (ITT) analysis of the primary endpoint of virologic cure was assessed using binomial exact 95% confidence intervals (CIs) and χ2 testing.
The study enrolled 456 participants (152 in each of three groups: HC+AZ, HC, placebo) between 13 April and 1 August 2020. HC+AZ, HC, and placebo groups had 6 (3·9%), 7 (4·6%), and 9 (5·9%) participants go off study medications before completing the medication course (p = 0·716). Day six PCR results were available for all 152 HC+AZ participants, 149/152 (98·0%) HC participants, and 147/152 (96·7%) placebo participants. Day six ITT analysis found no difference (p = 0·821) in groups’ proportions achieving virologic cure: HC+AZ 16/152 (10·5%), HC 19/149 (12·8%), placebo 18/147 (12·2%). Day 14 assessment also showed no association (p = 0·072) between study group and viral cure: HC+AZ 30/149 (20·1%,), HC 42/146 (28·8%), placebo 45/143 (31·5%). There were no serious adverse events.
Interpretation
HC±AZ does not facilitate virologic cure in patients with mild or asymptomatic Covid-19.
Q-PROTECT's main finding was a failure of HC±AZ to have any salutary effect in mild or asymptomatic SARS-CoV-2 infection. In a group of relatively young, healthy participants (virtually all males) enrolled within 24 h of testing positive for the virus, HC±AZ neither improved virologic cure rates nor reduced viral burden. The therapeutic failure of HC±AZ was clear at both day six and day 14.
A promising March 2020 report from Marseille focused interest on HC±AZ to speed viral clearance and effect clinical improvement. Within a few weeks, though, neither of these benefits were found by another French group assessing a small (n = 11) series of hospitalized patients.The ensuing months have seen substantial criticism of both the initial Marseille study and the overall evidence base regarding use of HC±AZ for Covid-19.
HC's performance with respect to post-exposure Covid-19 prophylaxis was assessed by Boulware and colleagues in an RCT instituting therapy within four days of high-risk exposure. Even with relatively high doses (1400 mg on day one, followed by 800 mg daily for days two through five) HC did not reduce rates of SARS-CoV-2 viral detection or (in the relatively large proportion of patients for whom there was no viral testing) development of Covid-19 symptoms.
With regard to HC treatment of mostly mild or asymptomatic cases, the Marseille group reported their ongoing open-label treatment results in May 2020; their non-controlled series (numbering 1061) continued to be favorable, with 92% having good clinical outcome and virologic cure. A few months later, a July 2020 open-label RCT from Catalonia arrived at a different conclusion: in non-hospitalized cases HC improved neither symptoms nor viral load. The same month, a double-blind North American RCT of adult outpatients with early Covid-19 diagnosis identified no clinical benefit with HC.
For hospitalized cases with mainly mild or moderate disease, two Chinese open-label trials reported in May 2020 that HC failed to speed clinical improvement or virologic cure.The same month, though, an open-label study of intubated patients in Wuhan found that HC reduced mortality via attenuation of cytokine storm.Three other May 2020 observational cohort studies, two from the USA and the other from France, failed to identify HC benefit. Furthermore, the analysis from New York suggested that the combination of HC+AZ was associated with increased risk of death from cardiac arrest. Editorial commentary began to emphasize need for careful consideration of risks and benefits when considering Covid-19 treatment with QT-prolonging drugs.
By June 2020, the balance of evidence supported a case against treatment of Covid-19 cases with HC±AZ. An international registry-based study of hospitalized Covid-19 cases identified increased risk of harm (due to ventricular dysrhythmia) in patients receiving HC or HC+AZ. The RECOVERY investigators announced withdrawal of the HC arm from their large-scale adaptive RCT. June also saw the USA's Food and Drug Administration (FDA) warning of unfavorable risk:benefit ratio with use of HC outside the hospital setting.
In July 2020, there emerged more conflicting evidence on HC use in hospitalized Covid-19 cases. Preliminary analysis by WHO's Solidarity investigators prompted HC's removal from their RCT, and an open-label Brazilian RCT concurred in finding no HC clinical benefits. However, two other reports, one from the USA and one from Marseille, left open the possibility of a role for HC+AZ in Covid-19.
From the USA, Arshad and colleagues’ July 2020 observational cohort study reported that HC (and similarly, the combination HC+AZ) improved mortality in patients hospitalized with Covid-19. The Michigan group found that AZ alone did not improve outcome, and there was no statistically significant benefit to adding AZ to HC. Favourable findings from the USA were echoed by the Marseille group, whose HC+AZ study population (now numbering 3119) spanned the acuity spectrum. The non-randomized Marseille series, which now included patients (n = 618) not treated with HC+AZ, found that HC+AZ cases had improved clinical outcomes and shorter duration of viral shedding.
As of 1 August 2020, the date of closure of enrollment in Q-PROTECT, existing data on HC±AZ use in hospitalized Covid-19 cases seems weighted toward the negative. However, as an early August commentary by Cohen states, the question of HC's potential utility in Covid-19 has not been definitively answered.There is a void in the existing evidence base that is filled by the current study.
In its blinded RCT design, Q-PROTECT differs from all but two of the preceding studies (both of which were published by the same group of North American investigators). The preponderance of the HC Covid-19 evidence – even the largest, high-quality trials such as RECOVERY and Solidarity – comes from observational or open-label designs and addresses treatment in hospitalized patients.
It is noteworthy that one of the two double-blinded Covid-19 HC RCTs addressed post-exposure prophylaxis only. The other was limited by performance of SARS-CoV-2 testing in only 58% of participants. While both of the blinded trials undoubtedly advanced the state of Covid-19 knowledge, neither assessed the concrete endpoint of virologic cure in a PCR-positive Covid-19 population. Q-PROTECT is the first double-blinded RCT that assesses in virtually all of its participants, an objective virologic endpoint in cases (those with mild or no symptoms) in whom virologic clearance is critical to pandemic control.
It is not the case that virologic cure is more important than clinical outcomes, but Q-PROTECT's laboratory-assessed endpoints fill a gap in the blinded-RCT Covid-19 evidence base. Specifically, a blinded RCT could inform national decisions on utility of HC±AZ to expedite viral clearance and thus reduce transmission. When Q-PROTECT commenced in mid-April 2020, approximately 50,000 people in Qatar had been tested for Covid-19. There had been over 3000 positive SARS-CoV-2 results and seven deaths, with 252 new cases in the 24 h prior to study commencement. As enrollment closed in August 2020, the Covid-19 epidemic in Qatar was a few months past its peak but the daily PCR-positive n was still over 200. Approximately a half-million Covid-19 tests had been done in the country between March and August, with over 100,000 positive results and a death rate of roughly 1 in 1000. Q-PROTECT set out to determine whether HC±AZ could expedite viral clearance and thus likely reduce transmission.
When considered in context of the existing evidence, the current study contributes data that can help fill the final gaps in knowledge about HC±AZ utility in Covid-19. Q-PROTECT's main strengths are inherent in its blinded RCT design. There was no indication of flaws in either randomization or blinding, and the effect estimates are unbiased and reasonably precise (with acceptable CIs). The point estimates for the primary endpoint of day six virologic cure were nearly equal for HC and placebo (with HC+AZ's cure proportions lower). The point estimates for both secondary endpoints were actually more favourable for placebo than for either HC or HC+AZ. There is thus no indication that accruing a larger sample would change Q-PROTECT's results.
There are a number of study limitations that restrict the conclusions drawn from Q-PROTECT. Perhaps the most important is in the emphasis on a non-clinical endpoint rather than patient-centered outcomes (e.g. symptoms, immunity). The intent was to shed light on a public health outcome – transmissibility – via a surrogate of virologic testing. The assumption that PCR negativity on naso- and oropharyngeal swab samples is linked to lesser likelihood of Covid-19 transmission is rational, but unproven and potentially nuanced. It is likely, for example, that Ct is an oversimplified surrogate for transmission risk, and that factors such as respiratory symptoms (e.g. sneezing) may be important contributors .
Just as negative PCR may not always mean zero transmission risk, a positive PCR could simply reflect detection of inactive (non-infectious) viral remnants. There remains a small (but non-zero) chance that Q-PROTECT's non-identification of post-treatment PCR detection differences could obscure a clinically important infectivity difference. The study is limited by the failure to address the possibility that there could be inter-group differences in infectivity of whatever viral particles were present after treatment.
Even if the use of PCR is accepted as an indicator of transmission risk, there remain unanswered questions that translate into Q-PROTECT limitations. Selection of another Ct endpoint (e.g. Ct >30) may accurately classify patients at very low risk of transmission; if this is the case then the endpoint of negative PCR (i.e. Ct >40 on the equipment used in this study) would be too stringent. No post hoc analysis was executed on different Ct cut-offs.
Other study flaws constituted threats to both internal and external validity. The main internal validity problems included dropouts and other losses to follow-up. The most substantial external validity threats related to the medication regimen and the study population.
A potentially significant internal validity issue was failure to confirm medication compliance (e.g. by having staff administer medications or by assaying drug levels). Since unreported non-compliance with study therapy would likely be associated with an active-drug regimen (e.g. from gastrointestinal side effects), it is possible that differential medication compliance biased Q-PROTECT toward a null finding.
Even if internal validity questions are resolved, there were a number of study limitations that affect external validity. Among the most important are related to Q-PROTECT's study population and the study's specific medication regimen.
Q-PROTECT's participants were nearly all male, and relatively young. Viral clearance rates are likely similar in females and males, but older patients may clear Covid-19 more slowly. Differential viral clearance in various races or ethnicities has not been well characterized. Q-PROTECT results are applicable only to patients similar to those enrolled in the current study.
The current study results applicability is also restricted in terms of medication regimen. While AZ use for asymptomatic or mildly symptomatic Covid-19 cases tends follow consistent dosing (500 mg on day one, 250 mg on days two through five), HC dosing varies widely across the Covid-19 evidence base. The Q-PROTECT regimen was selected in March 2020, to match the approach reported successful in Marseille. However, some studies have utilized higher HC doses in the initial days of therapy, and many studies use different daily maintenance doses or durations of therapy. For example, as compared to the one-week Q-PROTECT regimen of 200 mg HC three times daily, Arshad and colleagues and Mitja and colleagues both utilized a day one 800 mg dose followed by 200 mg twice daily for less than a week. Tang and colleagues, while also focusing on mild or moderate disease, administered a higher initial dose (1200 mg daily for three days) and a higher maintenance dose (800 mg) for a longer time frame (two to three weeks). In their post-exposure prophylaxis study, Boulware and colleagues also used a relatively high initial HC dose (1400 mg on the day of exposure).
In the Covid-19 evidence base, HC dosing levels do not invariably correlate with efficacy findings. This absence of definitive correlation does not exclude potential importance of dosing regimen. Expert reviewers have remarked that initial therapy with at least 800 mg may be necessary for viral clearance Physiologically based pharmacokinetic (PBPK) modeling has also utilized a day-one dosage of 800 mg, but overall PBPK recommendations are not substantially inconsistent with the dosing approach used in Q-PROTECT. Yao and colleagues used PBPK models to assess multiple regimens of HC SARS-CoV-2 in an in vitro (Vero cell) model. Their recommendation for a first-day loading dose of 800 mg followed by four daily doses of 400 mg was aimed at balancing safety and efficacy, but they did not assess a day-one loading dose of less than 800 mg. The overall approach suggested by PBPK modeling was not markedly different from Q-PROTECT's regimen: the current study provided a smaller day-one dose (600 mg rather than 800 mg) but a larger subsequent daily dose (600 mg rather than 400 mg). It is possible that a dosing regimen different from that of Q-PROTECT could produce different results.
If it is the case that early exposure to HC is needed in order for the drug to effectively inhibit viral replication, then dosing issues may be overshadowed by the fact that the medication was given too late in the course of illness. This hypothesis, while not able to be tested in the current dataset (Q-PROTECT is underpowered for the assessment), seems an unlikely major confounder. Medication was instituted rapidly after PCR – within hours, and never more than 24 h – in patients with disease that was either mild or asymptomatic. However, it must be acknowledged that the negative findings of Q-PROTECT do not necessarily rule out HC benefit if the drug is given earlier in the course of infection.
Any benefit from HC must be weighed against drug-associated adverse effects. As used for Covid-19, HC's most common side effects are gastrointestinal and rarely severe . Serious adverse events (defined as mortality or major non-transient morbidity) did not occur in Q-PROTECT and were also rare or absent in other HC RCTs However, all reports acknowledge the most serious adverse effect of HC±AZ as QT prolongation with associated risk of dangerous dysrhythmias such as torsades de pointes (TdP).
Q-PROTECT was not powered to assess rare events such as TdP. Neither TdP nor any ventricular dysrhythmia was seen. However, in considering large-scale use of HC±AZ, even rare risks have important population-level implications. Q-PROTECT's adverse-effect results should not be construed as confirming safety of HC±AZ. Exploration of rare but significant adverse effects remains the province of larger studies that are more focused on QT assessment.
The study's daily ECGs were judged to provide an acceptable safety margin for detection of significantly prolonged QT or concerning dysrhythmia. However, there remained important QT-related study limitations. The study methodology did not guarantee that for each participant, ECGs would be regularly timed (a few hours after medication dosing), performed by the same machine, and undergo cross-validation (since machine algorithms can over- or underestimate QT). Study participants’ QT monitoring in the quarantine environment was characterized by use of different ECG machines, irregularly timed ECG execution, delayed availability of hardcopy ECG tracings, and lack of cross-checking of machine-reported QT. The study data are therefore not suitable for analysis of QT prolongation associated with HC±AZ. Other investigators using appropriately rigorous methodology have already quantified QT prolongation by HC and AZ, confirming the fact that whatever benefits HC±AZ may bring, come with attendant risk.
The lessons of Q-PROTECT must be considered in light of the trial strengths and weaknesses, the medication risks and benefits, and the existing evidence base. Taking all of these factors into account, the investigators conclude that HC±AZ shows no sign of usefulness in the population studied, and that there is low likelihood of undiscovered drug benefits outweighing therapeutic risks.
Reference & Source information: https://www.thelancet.com/
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