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Hospitalized COVID-19 patients treated with hydroxychloroquine (HCQ) alone, or HCQ plus the antibiotic azithromycin, had significantly lower mortality than those not receiving the drugs, according to a study released this month in New Microbes and New Infections.

Researchers in Belgium that just 16.7% of COVID-19 patients given HCQ, with or without azithromycin, died within 28 days compared to 25.9% among those not taking HCQ — a 35% lower mortality.

After adjusting for age differences, the risk of death was still 24% lower for HCQ-treated hospitalized patients.

The survival benefit was seen across all ages and was statistically significant.

The results support the efficacy of HCQ and azithromycin in improving outcomes for hospitalized COVID-19 patients. This contrasts with earlier studies using dangerously high HCQ doses that found no benefits.

Who participated in the study?

Led by Dr. Gert Meeus, a nephrologist at AZ Groeninge Hospital, Kortrijk, Belgium, researchers collected data from March 16 to May 20, 2020 — the first few months of the pandemic.

They compared outcomes for 352 COVID-19-positive, HCQ-treated adults hospitalized at AZ Groeninge Hospital with those of 3,533 patients across Belgium who did not receive the drug.

Treated patients averaged 69.7 years versus 73.1 years for the control group. While this age difference favors the younger subjects who face less risk from the virus, this factor was more than offset by the treatment group’s higher incidence of high blood pressure, diabetes, liver and lung diseases, and weakened immunity.

Treated subjects were also more obese — a COVID-19 risk factor — with lower blood oxygen (suggesting severe illness) and higher C-reactive protein levels. C-reactive protein is a blood marker for inflammation and poor COVID-19 outcomes.

During the 28 days following initial treatment, 16.7% of patients who received HCQ, either alone or with azithromycin, died compared with 25.9% in the control group.

How was HCQ administered?

For the study, 299 patients (85%) received HCQ plus azithromycin versus 53 who took HCQ alone. Researchers only prescribed the antibiotic when they suspected bacterial pneumonia. Data for HCQ alone and HCQ plus azithromycin were combined.

Subjects received HCQ as two 400-milligram doses on day one and two 200-milligram doses on days two through five.

Patients younger than 75 years received 500 milligrams of azithromycin for five days. Older patients took 500 milligrams on day 1 and 250 milligrams per day for four days.

88% of patients received the full treatment course but 12% took the drugs for less time, at the caregiver’s discretion, due to side effects or reaching a terminal condition.

Otherwise, side effects observed in 197 patients were mild and mostly stomach issues. One patient had hallucinations and two developed a skin rash.

Thirteen patients dropped out of the study due to side effects, including 4 of 15 who developed heart muscle abnormalities — despite an earlier study reporting an association between HCQ and lower cardiovascular risk.

Nine patients dropped out because of digestive upset. One patient developed an abnormal but nonfatal post-study heart rhythm, but no treated patients experienced sudden death or irregular heartbeat during the study.

How the drugs work

HCQ and azithromycin work together to eliminate the COVID-19 virus, but the drugs may benefit patients in other ways.

Both drugs act on the immune system in ways that may suppress the COVID-19 cytokine storm responsible for much of COVID-19-related illness and death.

HCQ may also prevent blood clots in COVID-19 patients, while azithromycin may prevent additional, non-lung bacterial infections.

HCQ was approved in the U.S. in 1955 to treat malaria, but because of its anti-inflammatory effects it is also prescribed to adults to treat autoimmune diseases like lupus and rheumatoid arthritis.

Most serious side effects — including retinopathy, which causes blindness — occur after years of use, while COVID-19 treatments generally last for less than one week.

The World Health Organization lists HCQ as an “essential medicine” based on its “safety, efficacy and public health relevance.”

Study strengths and weaknesses

Meeus designed his study and interpreted his findings to include results that may not have supported the “safety and efficacy” of HCQ.

For example, all patients receiving at least one dose of HCQ were included in the treatment group regardless of whether they completed the study. One dose of HCQ was unlikely to affect their survival, but including such patients would have increased mortality numbers in the treatment group, thereby underestimating HCQ survival benefits.

Excluding very sick patients in a survival study tends to make data appear stronger because fewer deaths invariably occur among healthier subjects. Meeus and coworkers did not do this.

Meeus’ results also likely underestimated the benefits of HCQ treatment by reviewing patients only after hospitalization, when they were already quite sick. COVID-19 treatment experts stress the importance of treatment before patients reach this stage.

This retrospective study associated a current outcome (death) with an earlier effect (receiving HCQ). Retrospective studies are less capable of establishing causation than prospective studies that first look at the intervention or cause and only later for effects.

Another potential study shortcoming involves the statistics investigators chose to report HCQ’s benefits. A reduction in deaths from 25.9% to 16.7% is a 36.5% decrease, but the effect is smaller when survival, not death, is the outcome measured.

Death rates of 25.9% and 16.7% mean that 83.3% of treated and 74.1% of untreated patients survived, for an overall survival benefit under 10%.

Reporting relatively large differences between two small numbers is a common strategy for amplifying modest clinical benefits.

Meeus did not account for the many observational studies carried out by such doctors as Didier Raoult, Vladimir Zelenko, Pierre Kory, Peter McCullough and others using HCQ with azithromycin and/or zinc to treat COVID-19 beginning in 2020 — some with very large practices — all demonstrating significant benefits with early treatment.

He also did not review early treatment randomized control trials or the many other studies showing clear benefits of HCQ treatment.

Conclusion: ‘remarkable’ results

The authors described their results as “remarkable” since large HCQ studies during the first pandemic year showed no benefit.

However, where Meeus and co-workers used HCQ at standard doses, the earlier trials used a fourfold higher total dose, including an initial dose seven times higher than the maximum approved dosage.

For example the WHO “Solidarity” and U.K. “Recovery” clinical trials used HCQ dosages that were considered fatal.

According to Meeus, other studies (see here, here, and here) using more reasonable HCQ dosing failed because they did not recruit enough subjects to show a statistically significant effect.

One of these studies found a 44% reduction in death at 28 days but included too few patients to be able to claim an HCQ benefit.

Image legend: Percentage of patients who died in the HCQ group (white bars) vs. the no-HCQ group (black bars) by age group. A survival benefit was seen in all age groups. While about 2.5% of untreated 31- to 44-year-olds died during the study, no treated patients in this age group died. Credit: Gert Meeus et al.

Meeus concluded:

“Our study suggests that, despite the controversy surrounding its use, treatment with hydroxychloroquine and azithromycin remains a viable option. The favorable results and reassuring safety data support the need for adequately powered confirmatory randomized controlled trials using low dose hydroxychloroquine plus azithromycin.

“Given the pandemic emergency it is reasonable to give this treatment the benefit of the doubt pending the results of these trials or the advent of better treatment options.”