Doctor and activist

COVID-19 Does Hydroxychloroquine and Azithromycin treatment work? 2/4/20

This is now a current question because of a French trial. When a new disease comes there is a rush to test existing substances to see if they work. When AIDS arrived, many drugs were tested. One drug, acyclovir was found to help. Acyclovir had been developed as an anti-leukaemia drug but had not been successful and so had never been patented. Glaxo patented it and made a fortune. Quinine, a drug derived from the bark of a South American tree had been used against malaria for years, and its derivative Chloroquine was the mainstay of anti-malarial prevention and treatment in WW2 and since. There does not seem to be any theoretical basis for believing that it would work against COVID-19. Chloroquine works on the asexual stage of the malarial parasite when it destroys haemoglobin in red cells to reproduce. The parasite splits haemoglobin into a haeme group and a protein component. It feeds off the protein component and detoxifies the haeme group by turning it into a soluable form, haemozion. Chloroquine acts by inhibiting the enzyme that creates haemozoin, and the parasite is killed by the haeme group which is toxic to it. (Hempelmann E, Parasitology Research 2007 100:671-6). This has nothing to do with viral replication and chloroquine has no activity against other viruses. Researchers in Marseilles have tried hydroxychloroquine, a similar drug with fewer side effects, against COVID-19. The trial has very modest numbers; 26 patients were treated and compared to 16 controls. The criteria for the trial was that the patients were over12 years old and had documented COVID-19 on a nasopharyngeal swab. They were treated for 14 days with hydroxychloroquine orally at 200mg 3 times a day for 14 days. The primary end point of the study was defined as virological clearance of the nose swab at 6 days. (i.e. no virus detected in a nose swab). Only 20 of the 26 were treated as 6 were lost; 3 went to ICU, 1 died, 1 left hospital and 1 stopped due to side effects. So it was 20 treated v. 16 controls. Patients were in 3 categories; Asymptomatic 16% (=6/36patients), Upper Respiratory, defined as pharyngitis and laryngitis 61% (=22/36), and lower respiratory defined as pneumonia proven by CT scan 22% (8/36). The control group were matched for gender and dates from the onset of symptoms, but the treated group were average age 51 as against the controls who were average 37. 6 patients were given azithromycin, a macrolide antibiotic to stop superinfection by bacteria. Superinfection is when a second opportunistic infection comes to a weakened patient. In this case the lungs are already damaged by the virus and the fluid there is a good culture medium for bacteria. It might be presumed therefore that the sicker ones were the ones that got azithromycin. At day 6, 100% of the patients on hydroxychloroquine and azithromycin had cleared the virus (6/6), and 57% of hydroxychloroquine alone (8/14), which together was 70%(14/20) of the treated patients. The control group only 12% (2/16) had cleared the virus. The clearing of the virus from the pharyngeal swab in 3-6 days is contrasted with Chinese data which shows virus shedding for a mean time of 20 days. Interestingly the patient who died on Day 3 and was excluded from the trial had also cleared the virus from his pharynx on Day 2. This raises the question as to whether clearing virus from the pharynx on a throat swab is a good proxy for probability of cure. The study has gone on long enough to determine this. So the question is, ‘Should this treatment be tried?’ The answer is that there is not enough data to make a definitive statement, but if you had coronavirus, you might as well try, just as you would probably take Vitamin C and zinc. But I am sceptical until there are more trials because there is no theoretical reason why it should work- the ‘common sense test’. On Friday, 27/3/20 the WHO started a big online trial called SOLIDARITY to test 4 different treatments: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two HIV drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses. The HIV combination was tried in China and found not to work, but the WHO wants to give it bigger trial. The world is watching and waiting. The trial paper is at: Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949 This is now a current question because of a French trial. When a new disease comes there is a rush to test existing substances to see if they work. When AIDS arrived, many drugs were tested. One drug, acyclovir was found to help. Acyclovir had been developed as an anti-leukaemia drug but had not been successful and so had never been patented. Glaxo patented it and made a fortune. Quinine, a drug derived from the bark of a South American tree had been used against malaria for years, and its derivative Chloroquine was the mainstay of anti-malarial prevention and treatment in WW2 and since. There does not seem to be any theoretical basis for believing that it would work against COVID-19. Chloroquine works on the asexual stage of the malarial parasite when it destroys haemoglobin in red cells to reproduce. The parasite splits haemoglobin into a haeme group and a protein component. It feeds off the protein component and detoxifies the haeme group by turning it into a soluable form, haemozion. Chloroquine acts by inhibiting the enzyme that creates haemozoin, and the parasite is killed by the haeme group which is toxic to it. (Hempelmann E, Parasitology Research 2007 100:671-6). This has nothing to do with viral replication and chloroquine has no activity against other viruses. Researchers in Marseilles have tried hydroxychloroquine, a similar drug with fewer side effects, against COVID-19. The trial has very modest numbers; 26 patients were treated and compared to 16 controls. The criteria for the trial was that the patients were over12 years old and had documented COVID-19 on a nasopharyngeal swab. They were treated for 14 days with hydroxychloroquine orally at 200mg 3 times a day for 14 days. The primary end point of the study was defined as virological clearance of the nose swab at 6 days. (i.e. no virus detected in a nose swab). Only 20 of the 26 were treated as 6 were lost; 3 went to ICU, 1 died, 1 left hospital and 1 stopped due to side effects. So it was 20 treated v. 16 controls. Patients were in 3 categories; Asymptomatic 16% (=6/36patients), Upper Respiratory, defined as pharyngitis and laryngitis 61% (=22/36), and lower respiratory defined as pneumonia proven by CT scan 22% (8/36). The control group were matched for gender and dates from the onset of symptoms, but the treated group were average age 51 as against the controls who were average 37. 6 patients were given azithromycin, a macrolide antibiotic to stop superinfection by bacteria. Superinfection is when a second opportunistic infection comes to a weakened patient. In this case the lungs are already damaged by the virus and the fluid there is a good culture medium for bacteria. It might be presumed therefore that the sicker ones were the ones that got azithromycin. At day 6, 100% of the patients on hydroxychloroquine and azithromycin had cleared the virus (6/6), and 57% of hydroxychloroquine alone (8/14), which together was 70%(14/20) of the treated patients. The control group only 12% (2/16) had cleared the virus. The clearing of the virus from the pharyngeal swab in 3-6 days is contrasted with Chinese data which shows virus shedding for a mean time of 20 days. Interestingly the patient who died on Day 3 and was excluded from the trial had also cleared the virus from his pharynx on Day 2. This raises the question as to whether clearing virus from the pharynx on a throat swab is a good proxy for probability of cure. The study has gone on long enough to determine this. So the question is, ‘Should this treatment be tried?’ The answer is that there is not enough data to make a definitive statement, but if you had coronavirus, you might as well try, just as you would probably take Vitamin C and zinc. But I am sceptical until there are more trials because there is no theoretical reason why it should work- the ‘common sense test’. On Friday, 27/3/20 the WHO started a big online trial called SOLIDARITY to test 4 different treatments: an experimental antiviral compound called remdesivir; the malaria medications chloroquine and hydroxychloroquine; a combination of two HIV drugs, lopinavir and ritonavir; and that same combination plus interferon-beta, an immune system messenger that can help cripple viruses. The HIV combination was tried in China and found not to work, but the WHO wants to give it bigger trial. The world is watching and waiting. The trial paper is at: Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949

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