treatment and prevention options for covid -19: evidence ... · patients in hcq group were given...

Treatment and prevention options for COVID-19: evidence and process against myths and hype

Andy GrayDivision of PharmacologyDiscipline of Pharmaceutical Sciences

PSSA Pretoria branch webinar April 2020 1

Learning objectivesAfter the webinar, attendees will be able to:1. Describe the processes being followed in South Africa to develop evidence-based guidelines for COVID-19.2. Identify the potential pharmacological options for treatment and prevention of COVID-19.3. Discuss the current state of evidence for potential pharmacological options. 4. List some of the areas of future research.


Background


• Global pandemic of a novel coronavirus (SARS-CoV-2), which first emerged in Wuhan, China in late December 2019

• Now close to 3 million cases of COVID-19, and over 200 000 deaths, globally

SA figures (28 April 2020)


https://sacoronavirus.co.za/

Initial presentation


Progression 80% of symptomatic patients develop mild

disease 15% develop severe disease (with

hypoxaemia, dyspnoea and tachypnoea) 5% become critically ill (with respiratory

failure, septic shock and/or multi-organ dysfunction)



Preventing acquisition

• Vaccine• Non-specific enhanced

immune response (BCG)• ARBs

Inhibiting replication

• Remdesivir• Oseltamivir• Lopinavir/ritonavir

Altering the immune response

• Hydroxychloroquine/chloroquine• Tocilizumab• Corticosteroids

• Azithromycin• IVIG• Interferons• Convalescent plasma

Understanding the clinical pressure to do

something, especially in severe cases, or those

presumed to be at risk of severe disease

(and death)


A common interpretation of off-label use and compassionateuse of drugs is that is that if the patient died, theydied from the disease, but if the patient survived, theysurvived because of the given drug. This is not true

In addition to the risk of harming patients without the possibility to even detect the magnitude of harm, the administration of off-label drug use, compassionate drug use, and uncontrolled studies during a pandemic also could discourage patients and clinicians from participating in RCTs, hampering any knowledge that could be gained about the effects of the drug being tested.

Business unusual


Rapid appraisals


http://www.health.gov.za/index.php/national-essential-medicine-list-committee-nemlc/category/633-covid-19-rapid-reviews

There is no current evidence from RCTs to recommend any specific treatment for patients with suspected or confirmed COVID-19 infection. This is an area of active study. Candidate drugs undergoing investigation include remdesivir, lopinavir/ritonavir, chloroquine, interferon, and toculizumab. To date, published clinical data on most of these agents consists largely of in vitro studies, with little or no human data. Hence we do not know whether these medicines benefit or cause harm to patients with COVID-19.


Current advice Where possible, consideration should be given

to enrol hospitalized patients in clinical trials. This provides both adequate monitoring and ethics oversight, and affords the opportunity to contribute to the therapeutics evidence base for future patients.

Where investigational therapeutics are given outside of a clinical trial, this should be done under the Monitored Emergency Use of Unregistered Interventions (MEURI) framework.


MEURI framework Data providing preliminary support for the intervention’s

efficacy and safety are available, at least from laboratory or animal studies.

The relevant human research ethics committee has approved the therapeutics’ use.

The patient’s informed consent is obtained. Adequate resources are devoted to minimizing the

therapeutics’ risk. The results of the intervention are documented and

shared with the wider medical and scientific community.


Concomitant medicines ACE-inhibitors and ARBs NSAIDs Corticosteroids


Pending further evidence we therefore do not recommend switching patients off ACE-I or ARBs unless there are other medical reasons to do so.

The evidence regarding nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 is similarly lacking. Nonetheless, where short-term fever or pain relief is required, it may be prudent to use drugs from other classes, such as paracetamol. For patients requiring NSAIDs for other indications however, the evidence is not definitive enough to recommend discontinuation.

Do not routinely give systemic corticosteroids for treatment of COVID-19 unless they are indicated for another reason.

Exploring one example


A total of 135 hospitalized patients with COVID-19 were enrolled. The median age was 47 years (IQR 36–55), and there was no significant gender difference (53.3% men).

A case series – uncontrolled, observational


All of the patients received antiviral therapy (135 [100%] (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [26.7%]). In addition, many patients received traditional Chinese medicine (124 [91.8%]). It is suggested that patients should receive Kaletra early and should be treated by a combination of western and Chinese medicine.

Among the 135 patients, only 1 patient died


In 80 in-patients receiving a combination of hydroxychloroquine and azithromycin we noted a clinical improvement in all but one 86 year-old patient who died, and one 74 year-old patient still in intensive care unit.


We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Centre. The patients were randomised 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only.

Under-powered RCT; many confounders


The test group received conventional treatment plus oral hydroxychloroquine sulphate 400 mg, once/d, for 5 d; the control group received only conventional treatment, including bed rest, oxygen inhalation, symptomatic support treatments, using the antiviral drugs recommended in the "Diagnosis and Treatment Protocol"[,] such as alpha interferon nebulization, oral lopinavir/ritonavir (Creizil), etc., where necessary[,] antibacterial drugs, etc.

An early attempt at an SR


We included six articles (one narrative letter, one in-vitro study, one editorial, expert consensus paper, two national guideline documents) and 23 ongoing clinical trials in China.


We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19.

Observational, but adjusted using propensity scores


Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group.


This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Patients were allocated to receive high-dosage CQ (ie, 600mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450mg twice daily on day 1 and once daily for 4 days).

Interim analysis, but ….


We were not able to independently assess the toxic role of CQ because all patients were already using azithromycin, as per hospital protocol.

In this phase IIb randomized clinical trial of 81 patients with COVID-19, an unplanned interim analysis recommended by an independent data safety and monitoring board found that a higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation.


For now, except for supportive measures, infection with SARS-CoV-2 is “essentially untreatable.”


Preventing acquisition

• Vaccine• Non-specific enhanced

immune response (BCG)• ARBs

Inhibiting replication

• Remdesivir• Oseltamivir• Lopinavir/ritonavir

Altering the immune response

• Hydroxychloroquine/chloroquine• Tocilizumab• Corticosteroids

• Azithromycin• IVIG• Interferons• Convalescent plasma

So far, trials are being stopped early (e.g. for toxicity) or results are being described as

“disappointing”


The study is a double-blind, randomised, placebo-controlled trial that will be conducted in health care settings. After obtaining fully informed consent, the investigator will recruit healthcare workers, or other individuals at significant risk who can be followed reliably for 5 months. 40,000 participants will be recruited and the investigator predict an average of 400-800 participants per site in 50-100 sites.

Conclusion There is no current evidence from RCTs to recommend any specific

treatment for patients with suspected or confirmed COVID-19 infection.

Where possible, consideration should be given to enrol hospitalized patients in clinical trials.

Off-label use of any medicine, for treatment or prevention of COVID-19, carries risks.

Diverting stocks of registered medicines also places those who currently use them for other indications at risk of shortages.

BUT …. anything and everything can change, tomorrow….colchicine, estrogen (for men), nicotine patches….new clinical evidence (and better quality)….so, stay informed, and be the voice of reason


treatment and prevention options for covid -19: evidence ... · patients in hcq group were given...

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