As the COVID-19 pandemic moves into its 10th month, greater patient survival suggests that treatment of severe disease has improved. How much of this improvement is due to better supportive care and how much to pharmaceuticals is a matter of debate. Given the huge effort that the biomedical community has put into finding drugs to treat COVID-19, with thousands of trials completed and ongoing, it's worth taking stock of the evidence for what has worked and what has not.
The hunt for COVID-19 treatments has become extraordinarily politicised, and no more so than with the aminoquinoline drugs chloroquine and hydroxychloroquine. Early observational studies suggested a beneficial effect of treatment with these cheap drugs, leading to acclamation by US President Trump. However, randomised controlled trials (RCTs) in hospitalised patients have shown no effect of hydroxychloroquine in reducing mortality. One RCT hinted at an effect when used as post-exposure prophylaxis, but this was not statistically significant. Unless new, high-quality evidence emerges, the aminoquinolines appear to have no future in the management of COVID-19. Remdesivir, an antiviral, was also the subject of White House fanfare. The US Government has attempted to corner the market for this costly drug but results of clinical trials are ambiguous. One review concluded that remdesivir may reduce time to clinical improvement and decrease mortality but had no effect on need for invasive ventilation or length of hospital stay. A subsequent RCT found no effect on mortality. Although approved to treat COVID-19 in the USA and Europe, conclusive evidence to support remdesivir is lacking. For other antivirals, there is no good evidence for efficacy of favipiravir, although it has been approved in Russia, and the lopinavir/ritonavir combination showed no clinical benefit in the UK RECOVERY RCT.
Immunomodulators to treat COVID-19 are being widely tested in clinical trials. Among the front-runners, evidence to support use of tocilizumab, a monoclonal antibody against interleukin-6 receptors, comes largely from observational studies. Roche, the manufacturer, has announced that the drug did not improve clinical status in a phase 3 RCT among patients with severe COVID-19-associated pneumonia. Similarly, good quality evidence on the use of convalescent plasma is still awaited. Large RCTs such as RECOVERY, which includes tocilizumab and convalescent plasma groups, should provide answers. Immunomodulators that do work are the corticosteroids. In the dexamethasone group of RECOVERY, deaths were reduced by 35% in ventilated patients and by 20% among those receiving oxygen only compared with those in the standard care group. An RCT of dexamethasone done in Brazil further supports the beneficial effect of the drug. The REMAP-CAP RCT of hydrocortisone—another corticosteroid—versus placebo in patients with severe COVID-19 showed a 93% improvement in the intervention group in days when organ support was not needed. Based on these findings, WHO guidelines recommend corticosteroids in patients with severe and critical COVID-19.
Is targeted treatment reducing deaths as the disease continues to sweep around the world? Where there has been a resurgence of COVID-19 cases to levels at least as high as when the pandemic first struck in the spring, such as in the USA, France, and Spain, it has not been followed by a comparable increase in deaths, nor of people requiring admission to hospital. Thus, treatment alone cannot be responsible for saving lives. Possible explanations for the recent disparity in cases and deaths include more widespread testing, meaning that the number of cases being detected is closer to the true burden of infection, whereas the accuracy of counting deaths remains unchanged; lower viral load at the point of transmission, and hence less severe disease, because of non-pharmaceutical measures such as mask wearing; and changes in the distribution of cases towards younger age groups. Data from England show that until recently cases have been fairly evenly distributed across all ages from 20 years upwards, but by the last 2 weeks of August cases in people aged 20–39 were about ten times the number in those aged 70 or more. Risk of COVID-19 death in young people is tiny compared with the elderly. However, cases in the young might yet spill over into older people, and the long-term consequences of non-fatal disease are unknown.
Whatever the reasons for apparent declining mortality, the impact of drug treatments on the COVID-19 pandemic is still limited. The massive research effort needs to bear fruit with a broader range of effective therapies.
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