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Real-World Evidence: The Case of Peru. Causality between Ivermectin and COVID-19 Infection Fatality Rate

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Abstract

In these eight Peruvian State analyses, Ivermectin distributions preceded sound reductions in excess deaths and case fatality rate (CFR). The variation in the number of detected cases nor the vulnerable population decrease can explain this reduction. Other possible explanations, such as cross-immunity with dengue, or mere causality, have been discarded due to their lack of consistency in this study. Treatment with ivermectin is the most reasonable explanation for the decrease in number of deaths and fatality rate in Peru. Its implementation in public policies is a highly effective measure to reduce the excess deaths and IFR of COVID-19.
Real-World Evidence: The Case of Peru
Causality between Ivermectin and COVID-19 Infection Fatality Rate
October 2020 / Juan Chamie
Introduction
In Peru, the widespread use of Ivermectin as a frontline treatment for COVID-19 has provoked a    
great deal of controversy. This South American country has been a pivotal point of reference
regarding the use of Ivermectin, a repurposed, antiparasitic medication. The Peruvian
government approved the use of Ivermectin, by decree, on May 8, 2020. The new Minister of
Health, Pilar Mazzetti, ratified the dispensing of Ivermectin, despite receiving numerous
requests to suspend it in September, 2020. These measures have aroused criticism among the
scientific community. They believe RCTs (Randomized Clinical Trials) are necessary to prove
it’s effectiveness against COVID-19 before distribution, overlooking the serious death toll in
Peru, one of the world’s highest from COVID-19.
It is important to verify the effect of Ivermectin interventions on the variations in mortality rate
and the associated viral lethality. If significant, another assessment is needed to determine if a
decrease in the number of new cases is due to a younger infected population, a substantial
reduction in the most vulnerable people, or other factors that could explain the variations.
Methodology
This study evaluated the impact of ivermectin interventions on the excess deaths and the case    
fatality rate (CFR). It assessed the impact of large distributions of ivermectin, reported by
regional authorities, on the variation in death toll associated with COVID-19 in the population
over 60 years of age.
The number of deaths associated with COVID-19 were calculated by comparing the numbers to
the median number of deaths in the same period for the 3 years prior to COVID-19.
In addition to focusing the assessment on the most vulnerable group, other factors that create
variations in mortality were analyzed, such as the number of positive cases in the same age
group and the reduction in the population group's size due to the deaths.
This study verified the ivermectin intervention statistics in the Situation Room database, official    
communications, and press releases that confirmed the drug's effective delivery and actions
related to its distribution. It obtained information regarding the mortality and fatality in the
selected age group from the registry of the National Computer System of Deaths (SINADEF),    
and the regional population, by age groups, from the National Institute of Statistics and
Informatics.
Conclusion
In these eight Peruvian State analyses, Ivermectin distributions preceded sound reductions in
excess deaths and case fatality rate (CFR). The variation in the number of detected cases nor
the vulnerable population decrease can explain this reduction. Other possible explanations,
such as cross-immunity with dengue, or mere causality, have been discarded due to their lack
of consistency in this study.
Treatment with ivermectin is the most reasonable explanation for the decrease in number of
deaths and fatality rate in Peru. Its implementation in public policies is a highly effective
measure to reduce the excess deaths and IFR of COVID-19.
 
Case 1: State of Loreto
Population: 1,027,559 ; Population over 60 years: 84,137
Intervention with ivermectin.
On May 24, the distribution of ivermectin by the Ministry of Health (MINSA) reached 28,545    
doses by the end of June, 2020. In July MINSA sent 22,000, in August 18,000, and in September      
68,217. MINSA sent a total of 136,762 doses: 0.13 doses per person in the state.
On May 11, 2020, Veterinarian Juan Huamanchumo made his first donation of 3,000 doses of  
Ivermectin, donating an additional 3,000 doses on May 20. This Ivermectin was received and
distributed among the population through the Loreto Medical College.
On May 12, 2020, a group of volunteers, ‘Loreto Solidario’ began a free campaign to supply
doses of Ivermectin to the entire population of Loreto. By June 18, 2020 the group led by     
Doctor Juan de Mihael vaccinated more than 15,000 adults with Ivermectin.
On May 11, 2020 the director of the Loreto hospital reported a decrease in the number of        
hospitalizations for COVID. By the end of June, the Regional Health Director closed the Hospital      
Centre created for the pandemic, due to a lack of patients.
Results in the population older than 60 years
Note, a decrease in deaths from the second week of May. The decrease in fatalities continued
until mid-July, and have not increased. Since the beginning of July, the daily number of deaths,
in the state of Loreto, is similar to the values presented before the pandemic.
The sharp decrease of deaths happened when only 0.69% of the population in this group had
died. The aggregate percentage of deaths from March to September is 1.62%
The case fatality rate was above 40% in April and May. It decreased to 28% in June, and since
July has remained below 4%.
Detected COVID-19 positive cases have remained stable between 400 and 500 cases per    
month, with the exception of August where they increased slightly, reaching 682.
Unexpectedly, the number of excess deaths went from 724 in May to 62 in July, a decrease of
91% in two months. These relative values of deaths went from 0.86% to 0.07%
The decrease in excess deaths from the second week of May forward coincides with the    
massive ivermectin interventions. There was no previous decrease in the cases to explain the    
drop in mortality, nor had there been a significant reduction in the vulnerable population. It had
only been reduced by 0.69%.
The sharp decrease in case fatality rate coincided with the distribution of Ivermectin, with an
associated decrease in hospital admissions.
 
Case 2. State of Ucayali
Population: 589,110; Population over 60 years: 51,639
Intervention with Ivermectin
On May 24, 2020, the distribution of Ivermectin by the Ministry of Health (MINSA) reached      
27,390 doses until the end of June. In July MINSA sent 59,167 doses, in August 7,288, and in      
September 6,300. MINSA sent a total of 100,144 doses: 0.17 doses per person in the state.
On May 7, the general manager at EsSalud, Federico Tong, announced the delivery of
ivermectin to be included in the protocol to treat COVID-19.
On May 26, two councilors and an official from the Departmental Government of Ucayali
announced the delivery of ivermectin to local authorities and health centers. Raúl Edgar Soto
Rivera, one of the counselors, confirmed as of May 18 they had delivered 500 doses of
ivermectin and had received a donation of 1,000 additional doses.
On July 7, the director of the Health Directorate of Ucayali, Willy Lora, shared with the media the        
protocol for the treatment of COVID in that region which included: Azithromycin, Ivermectin
drops and Paracetamol.
On June 18, Director of the Ucayali Assistance Network, Dr Francisco Samaniego, announced
the start of ivermectin production in the Ucayali region.
Results in the population older than 60 years
The sharp decrease of deaths happened when only 0.71% of the population in this group had
died. The aggregate percentage of deaths from March to September is 1.48%
The case fatality rate, which was above 20% in April, remained below 10% between May and
June. Since August it has remained below 3%.
Confirmed Positive COVID-19 cases decreased between May and June, reaching 822 in August,
the highest number since the start of the pandemic.
Unexpectedly, excess deaths went from 463 in May to 51 in July, a decrease of 89% in two
months. These relative values of deaths went from 0.90% to 0.10%
Between May and June, the decrease in excess deaths coincided with the distribution of
ivermectin. The variation in the number of positive cases is not related to the variation in    
deaths. There was no significant reduction in this population group to explain why the
vulnerable population had only been reduced by 0.71%.
The decrease in the case fatality rate coincides with the start of ivermectin programs.
 
Case 3: State of Piura
Population: 2,047,954 ; Population over 60: 234,250
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA), which began on May 24, 2020,
reached 59,590 doses by the end of June. In July, MINSA sent 47,500 doses; in August, 5,000
doses; and in September, 25,000 doses. MINSA sent a total of 137,090 doses, which amounted
to 0.07 doses per person in the state.
On May 21, the mayors of the province of Piura announced the purchase of ivermectin to be      
delivered to the population affected by the virus.
On May 31, a group of volunteers "Comando COVID" reported its campaign to deliver
ivermectin, for the treatment of COVID-19, free of charge, to people with limited resources.      
More than 12,000 doses have been delivered to date.
On July 3, the Piura government announced distribution of 100,000 doses of ivermectin to
health centers in the region.
The mayor of Piura, Juan José Diaz Dios, confirmed that by July 22, they had delivered 300,000
doses of ivermectin.
Results in the population older than 60 years
Beginning the last week of May, there was a decrease in the number of deaths. This decline
was steep through the end of June and has continued with a slight decline week after week.
The number of daily deaths in Piura has been stable since July, however, it continues to be
higher than average before the pandemic.
The decrease of deaths happened when only 0.53% of the population in this group had died.
The aggregate percentage of deaths from March to September is 1.41%.
The case fatality rate was around 30% until June. It decreased to 14% in July. Since August it is
below 10%.
Monthly, the COVID-19 cases detected have remained stable at approximately 1,400 since May.
However, in July there was a decrease in numbers due to a 30% reduction in testing.
Unexpectedly, monthly deaths went from 1,374 in May to 387 in July. A decrease of 72% in two      
months. The relative values of deaths went from 0.59% to 0.17% for this population group.
The decrease in the excess deaths at the end of May coincides with the distribution of      
ivermectin in the department. The variation in the number of positive cases does not explain      
the variation in deaths, nor can it be explained by a substantial reduction in this population
group, which had only decreased 0.53%.
The reduction in the case fatality rate that occurred as of July also coincides with the       
distribution of ivermectin in the Department's Health Centers.
 
Case 4: State of Tumbes
Population: 251,521 ; Population over 60: 28,166
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA) that began on May 24, 2020
reached 9,795 doses through June 14. In July MINSA sent 61,167 doses, and in August 3,000.
MINSA sent a total of 72,962 doses, amounting to 0.29 doses per person in the state.
June 9, the Governor of the Department and the Director of Health of the region announced that        
they have promoted the active search for COVID-19 patients who are given ivermectin as part
of the treatment.
June 27, The Governor of Tumbes, in a meeting with the Mayors of the Region, announced the       
implementation of the "Pharmacological Blockade" program in all the Districts of the      
Department, with an associated acquisition of 50 thousand doses of ivermectin.
Results in the population older than 60 years
In the first week of June, the number of deaths began to decline, with a further decline in the    
first week of August. The drop in fatalities continued week after week. The daily number of
deaths in Tumbes since mid-August is similar to the average number before the pandemic.
The decrease in the number of deaths occurred when 0.72% of this population group had died.
The aggregate percentage of deaths from March to September is 1.86%.
The fatality rate, which remained around 30% until June, decreased to 6% in July and 3% in
August.
COVID-19 cases from May to August have remained stable at between 180 and 315 cases.
Unexpected excess deaths went from 198 in June to 38 in August, a decrease of 81% in two
months. The relative values of deaths went from 0.70% to 0.13% in this population group.
The decrease in deaths that occurred from June coincides with the beginning of the
distribution of ivermectin in the department. The variation in the number of positive cases does    
not explain the variation in deaths, nor can it be explained by a substantial reduction in this    
population group, which had only been reduced by 0.72%.
The reduction in the case fatality rate as of July coincides with the expansion of the      
"Pharmacological Blockade" program where the central axis is ivermectin, throughout the state.
 
Case 5: State of La Libertad
Population: 2,016,771; Population over 60: 257,655
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA) that began on May 24, 2020
reached 42,355 doses through the end of June. In July MINSA sent 154,000 doses, in August
98,333, and in September 35,750. MINSA sent a total of 330,438 doses: 0.16 doses per person
in the state.
On July 23, the regional governor of La Libertad, Manuel Llempén reported he had distributed
40,000 doses of ivermectin among health centers in the region.
On July 20, the Government of La Libertad reported delivery of ivermectin to more than 30,000
people, including patients with COVID-19 and their families.
On August 4, the La Libertad Medical College requested termination of the ivermectin mass
distribution program, arguing that it generated false hopes. They also stated that deaths had
not been reduced. In an official communication on June 15, the regional entity had already
rejected the use of ivermectin and had recommended abstaining from its use.
Results in the population older than 60 years
In the second week of June, the number of deaths had slowed, and from the second week of      
July they began to decline. The decline in fatalities has continued week after week. The deaths
in La Libertad since the second week of September are similar to the values presented before      
the pandemic.
The decrease in the number of deaths occurred when only 0.74% of this population group had      
died. The aggregate percentage of deaths from March to September is 1.27%.
The fatality rate, which grew month by month until reaching 60% in June, rose to 25% in July , in  
August it was 13%, and in September 9.5%.
COVID-19 cases detected between June and August have increased slightly from 1,204 cases
in June to 1,394 in August. In September decreased to 1,155.
Unexpectedly, excess deaths went from 1,293 in June to 485 in August. A 62% decrease in two      
months. Between the same period, the relative values of deaths went from 0.50% to 0.19% in    
this population group.
By the end of June, the decrease in deaths coincides with the distribution of ivermectin in the       
department. The variation in the number of positive cases does not explain the variation in
deaths, nor can it be explained by a substantial reduction in this population group, which had
only been reduced by 0.74%.
The reduction in the case fatality rate began to appear in mid-June and coincided with the
distribution of ivermectin in the department's health centers. The fatality rate is higher than that
shown in other states. It is important to verify whether this higher fatality has been a
consequence of the regional medical college's rejection of ivermectin treatment.
 
Case 6: State of Arequipa
Population: 1,497,438 ; Population over 60: 212,228
Intervention with ivermectin
The distribution of Ivermectin by the Ministry of Health (MINSA) that began on May 24, 2020
reached 15,375 doses through the end of June. In July MINSA sent 185,000 doses, in August
25,000, and in September 33,000. MINSA sent a total of 258,375 doses, which amounted to
0.17 doses per person in the state.
On July 20, the Arequipa Health Network (La Red de Salud Arequipa) began delivery of
ivermectin to the population affected by the virus in its initial stage
On July 20, the 25 regional health centers began to deliver ivermectin, azithromycin and
Acetaminophen to all diagnosed patients.
On August 5, in an emergency meeting, the mayors of Arequipa agreed to manage the
purchase of one million doses of ivermectin for the treatment of patients infected by the
coronavirus.
Results in the population older than 60 years
In the first week of August, the number of deaths plummeted. It followed a steady decline in   
fatalities that has continued week after week. The deaths in La Arequipa at the end of
September are similar to values presented before the pandemic.
The decrease in the number of deaths occurred when only 1.19% of this population group had      
died. The aggregate percentage of deaths from March to September is 1.79%.
The case fatality rate, which grew month by month until reaching 20% in July. Since August it is
below 10%.
Detected COVID-19 cases grew exponentially from 346 cases in June to 3,447 in August. In
September cases decreased to 1,532 due less testing.
Unexpected excess deaths went from 1,728 in July to 243 in September, a 86% decrease in two
months. Between the same period, the relative values of deaths went from 0.86% to 0.16% in    
this population group.
The decrease in deaths that occurred from August coincides with the massive ivermectin
distribution program in the department. The variation in the number of positive cases does not
explain the variation in deaths, nor can it be explained by a substantial reduction in this
population group, which had only been reduced by 1.19%.
The reduction in the case fatality rate began to appear in August and coincided with the
distribution of ivermectin in the department's health centers.
 
Case 7: State of Moquegua
Population: 192,740 ; Population over 60: 29,157
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA) that began on May 24, 2020
reached 2,605 doses through the end of June. Between July 5 and 12, MINSA sent 20,000
doses; between july 26 and August 9, 116,667 doses; and on August 23, 25,000 doses. MINSA    
sent a total of 159,322 doses, which amounted to 0.83 doses per person in the state.
On July 10, the Moquegua Regional Hospital began the production of ivermectin The drug     
would be sent to health centers for the treatment of patients with COVID-19.
The Moquegua region received medical personnel and a large shipment of medicines on
August 5, with the purpose of starting its massive distribution as of August 6 as part of the
government program called "Operation Tayta."
According to the official medicine distribution records of the Ministry of Health, between
August 4 and 13, the national government distributed 28,000 doses of ivermectin in Moquegua.
On August 15, the Moquegua Development Fund delivered two thousand kits with Paracetamol,
Azithromycin and Ivermectin.
Results in the population older than 60 years
Starting the first week of August, the number of deaths began to plummet. The decline in   
fatalities has continued week after week. The deaths in Moquegua in September are similar to
those that occurred before the pandemic.
The decrease in the number of deaths occurred when 1.08% of this population group died. The
aggregate percentage of deaths from March to September is 1.76%.
The case fatality rate, which grew month by month reached 32% in June. It declined to 15% in
July, 8% in August and 4% in September.
Detected COVID-19 cases grew exponentially from 60 cases in June to 1,047 in August. In
September cases dropped following a decrease in testing.
Unexpectedly, excess deaths went from 309 in August to 29 in September, a decrease of 91%
in one month. The relative values of deaths went from 1.06% to 0.10% of this population group.
The decrease in deaths from August coincides with the massive ivermectin distribution
program in the department. The variation in the number of positive cases does not explain the      
variation in deaths, nor can it be explained by a substantial reduction in this population group,
which had only been reduced by 1.08%.
The reduction in the case fatality rate from July coincides with the production of ivermectin at
the regional hospital, and the other drug delivery campaigns.
 
Case 8: State of Cusco
Population: 1,357,075 ; Population over 60: 138,969
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA) that began on May 24, 2020
reached 10,828 doses through the end of June. In July MINSA sent 27,500 doses; in August,
50,000 doses; and in September, 62,375 doses. MINSA sent a total of 150,703 doses, which
amounted to 0.11 doses per each person in the state.
On June 15, the Adolfo Guevara Velasco National Hospital in Cusco received new medical
equipment and 600 doses of ivermectin for the treatment of COVID patients.
On August 15, 2020, the Cusco Health Directorate began the distribution of ivermectin among      
health centers in the region. One thousand daily doses was its initial production capacity.
On August 20, the regional director of Health in Cusco announced the distribution of 20,000     
ivermectin treatments.
Results in the population older than 60 years
In the last week of August, the number of deaths began to drop dramatically. Fatalities
decreased week after week. The daily number of deaths in Cusco in the second week of    
September is similar to the average number before the pandemic.
The decrease in the number of deaths occurred when only 0.40% of this population group had      
died. The aggregate percentage of deaths from March to September is 0.66%.
By June, the cumulative fatality rate was 16%. During July and August, the fatality rate had
been below 10%.
Detected COVID-19 cases grew exponentially, moving from 71 cases in June to 1,679 in
August. In September cases dropped following a decrease in testing.
Unexpectedly, excess deaths went from 725 in August to 165 in September. A decrease of 77%
in one month. The relative values of deaths went from 0.52% to 0.12% of this population group.
The decrease in deaths at the end of August coincided with the distribution of ivermectin in the      
department. The variation in the number of positive cases does not explain the variation in
deaths, nor can it be explained by a substantial reduction in this population group, which had
only decreased by 0.40%.
The reduction in the case fatality rate began in July and coincides with the distribution of
ivermectin by the Ministry of Health.
 
Control group: State of Lima
Population: 10,628,470 ; Population over 60: 1,648,028
Intervention with ivermectin
The distribution of ivermectin by the Ministry of Health (MINSA) that began on June 1, 2020    
only reached 4,066 patients by mid-July.
On August 20, 2020 the Ministry of Defense announced the ‘Mega Tayta Operation,’ its goal      
being to reach 500,000 COVID-positive patients by the end of the year. Lima was included in the      
program.
A recent Peruvian observational study showed that less than 10% (561) of Covid-positive
hospitalized patients in Lima received ivermectin as a treatment from April to July, out of a
sample of 5,683 patients.
Results in the population older than 60 years
During the first week of June, the number of deaths shortly dropped, then fatalities plateaued
until mid August. In September, the daily number of deaths in Lima was higher than any other
state of Peru.
The decrease in the number of deaths took place when 1.82% of the population group had died.    
The aggregate percentage of deaths from March to September was 2.02%.
The case fatality rate, which stayed around 20% from April to July declined in August, but it still
remains the highest among Peruvian States.
Detected COVID-19 cases remained stable at around 10,000 cases since April. In August cases
grew, following an increase in testing.
The deaths in the Lima districts showed the same growth in April and the same plateau from      
June. Lima showed a unified single wave.
Excess deaths remained stable between 6,000 and 7,000 from April to August. There was a    
50% decrease in September. The relative values of deaths were around 0.40% of this
population group.
There was no decrease in deaths between April and August, nor reduction in the case fatality
rate during this period.
 
Discussion
The correlation between the ivermectin interventions and the decrease in both excess deaths
and case fatality rate are quite strong and consistent in all the regions analyzed. Because the      
correlation is strong, the probability of this being caused by other factors is low.
The most certain way to rule out a correlation occurring by random chance is to find the same
correlation in several cases. This study has seen the correlation between interventions with
ivermectin and a decrease in excess deaths and the case fatality rate in eight Peruvian states.
Additionally, when analyzing two outcomes instead of one (excess deaths and CFR), a casual
result becomes even more implausible. In this manner, we discard accidental cause as an
explanation for the correlation.
Regarding external factors, we have already ruled out causality by a higher percentage of the
young population by including only people over 60 years of age in the study. We also ruled out
the variation in the number of cases when verifying that there was no decrease in these before
reducing mortality. We also ruled out a substantial reduction in the susceptible population
when confirming that in no case did deaths reduce this population by more than 2.0%.
Regarding susceptible population reduction at the time of the decrease in excess deaths and    
CFR, these values were unequal in the states analyzed. As an example, the population    
reduction in Arequipa was four times higher than the decrease in Cusco.
To rule out the possibility of a weaker strain of the virus having mutated throughout the    
Peruvian region, thereby conveying some degree of cross-immunity to COVID-19, Lima has
been included in the study as a control group. The excess deaths and CFT in the Peruvian
Capital remained stable for five months, between April and August.
Recently, a new theory emerged that some scientists say could explain the low mortality levels
in some regions. It is a cross-immunity with dengue that would explain the low levels of
mortality. This theory collapses here, by observing the high mortality rates in Peruvian states
such as Arequipa and Moquegua, where there haven't been dengue cases in the last 20 years.
The mortality rose with COVID cases and dropped after the intervention with ivermectin.
Conclusion
In these eight Peruvian State analyses, ivermectin distributions preceded significant reductions
in number of deaths and infection fatality rate. The variation in the number of detected cases
or a decrease in the vulnerable population can't explain the mortality and lethality
improvement. Likewise, other possible explanations, such as crossed immunity with dengue, or
mere causality, have been discarded here due to their lack of consistency.
Treatment with Ivermectin is the most reasonable explanation for the decrease in the death      
and fatality rate in Peru. Its implementation in public policy is a highly effective measure to
reduce the mortality and lethality of COVID-19.
 
Charts and tables
... For example, Peru had a very high death toll from COVID-19 early on in the pandemic. 128 Based on observational evidence, the Peruvian government approved ivermectin for use against COVID-19 in May 2020. 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. ...
... 128 Based on observational evidence, the Peruvian government approved ivermectin for use against COVID-19 in May 2020. 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. 128 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30+ days and of 75% at 45+ days. ...
... 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. 128 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30+ days and of 75% at 45+ days. 129 However, factors such as change in behavior, social distancing, and face-mask use could have played a role in this reduction. ...
Article
Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
... For example, Peru had a very high death toll from COVID-19 early on in the pandemic. 128 Based on observational evidence, the Peruvian government approved ivermectin for use against COVID-19 in May 2020. 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. ...
... 128 Based on observational evidence, the Peruvian government approved ivermectin for use against COVID-19 in May 2020. 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. 128 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30+ days and of 75% at 45+ days. ...
... 128 After implementation, death rates in 8 states were reduced between 64% and 91% over a two-month period. 128 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30+ days and of 75% at 45+ days. 129 However, factors such as change in behavior, social distancing, and face-mask use could have played a role in this reduction. ...
Preprint
Full-text available
Background Re-purposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with anti-viral and anti-inflammatory properties, has now been tested in numerous clinical trials.Areas of uncertainty We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemo-prophylaxis, among people with, or at high risk of, covid-19 infection. Data sourcesWe searched bibliographic databases up to April 25 2021. Two review authors sifted for studies, extracted data and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality.Twenty-four RCTs involving 3406 participants met review inclusion. Therapeutic Advances Meta-analysis of 15 trials found ivermectin reduced risk of death compared with no ivermectin (average Risk Ratio 0.38, 95% confidence interval (CI) 0.19 to 0.73; n=2438; I2=49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis (TSA) using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a TSA using the Biggerstaff-Tweedie method. Low-certainty evidence found ivermectin prophylaxis reduced covid-19 infection by an average 86% (95% CI 79% to 91%). Secondary outcomes provided less certain evidence. Low certainty evidence suggested that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ clearly favoured ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty.Conclusions Moderate-certainty evidence finds that large reductions in covid-19 deaths are possible using ivermectin. Employing ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.
... mg/kg orally (repeat on day 3). [1][2][3][4][5]62,[64][65][66][67][68][69][70][71][72][73][74] See Table 1, Figure 5 and ClinTrials.gov NCT04523831. ...
... • Highly recommended: Ivermectin 0.15-0.2 mg/kg orally (12 mg) and repeat on day 3 [1][2][3][4][5]62,[64][65][66][67][68][69][70][71][72][73][74]. It should be noted that ivermectin has potent anti-inflammatory properties apart from its antiviral properties. ...
... Alternative strategy is a dose of 12 mg within 24 hours of symptom onset and then repeated 24 hours later. [1][2][3][4][5]62,[64][65][66][67][68][69][70][71][72][73][74]. [1][2][3]64,[67][68][69][70][71][72][73][74][129][130][131][177][178][179][180][181][182][183][184] Note that ivermectin has potent antiviral and antinflammatory effects. ...
Article
Full-text available
This brief note introduces the reproduction of medical content, authored by Doctor Paul E. Marik. Dr. Marik is Professor of Medicine and Chief of Pulmonary Medicine and Critical Care at Eastern Virginia Medical School in Norfolk, Virginia (USA). Dr. Marik is an extremely qualified and experienced professional. The reprinting of the material was authorized by Dr. Marik himself on 12/02/2020. This material is relevant in the Brazilian scenario due to standardized procedures for patients infected with the coronavirus. Only 1 of the 5 files kindly provided by the author, in PDF format, was selected and reproduced as received, without any editing. Due to the pandemic's long duration, the Journal editors (who are not medical doctors) have already had the opportunity to monitor the development of the disease in more than one infected person. The type of treatment offered to patients seems to influence the course, duration, and severity of the disease. The treatments described in the materials below appear to be effective and have good results. The editors will refrain from making additional comments on the proposed methods not to influence anyone, restricting themselves to suggesting that they be discussed with the reader's trusted doctor in case of need or doubts. Complete, updated information and also translated into Portuguese are available at . We are grateful to Dr. Marik for his kindness in giving us his time in this troubled period.
... For example, Peru had a very high death toll from covid-19 early on in the pandemic. 120 Based on observational evidence, the Peruvian government approved ivermectin for use against covid-19 in May 2020. 120 After implementation, death rates in eight states reduced by 64-91% over a two-month period. ...
... 120 Based on observational evidence, the Peruvian government approved ivermectin for use against covid-19 in May 2020. 120 After implementation, death rates in eight states reduced by 64-91% over a two-month period. 120 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30 + days and of 75% at 45 + days. ...
... 120 After implementation, death rates in eight states reduced by 64-91% over a two-month period. 120 Another analysis of Peruvian data from 24 states with early ivermectin deployment has reported a drop in excess deaths of 59% at 30 + days and of 75% at 45 + days. 121 However, factors such as change in behaviour, social distancing, and face-mask use could have played a role in this reduction. ...
Preprint
Full-text available
Background Re-purposed medicines may have role in combating the SARS-CoV-2 virus. The antiparasitic medicine ivermectin, which has anti-viral and anti-inflammatory properties, has been tested in numerous clinical trials with promising results. Methods We assessed the efficacy of ivermectin treatment and/or prophylaxis among people with, or at high risk of covid-19 infection. We searched bibliographic databases up to February 2021 and two review authors sifted for studies, extracted data and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using GRADE approach. Findings Twenty-one RCTs involving 2741 participants met review inclusion. Meta-analysis of 13 trials found ivermectin reduced risk of death compared with no ivermectin (average Risk Ratio 0.32, 95% confidence interval (CI) 0.14 to 0.72; n=1892; I²=57%; low to moderate-certainty evidence. Low-certainty evidence found ivermectin prophylaxis reduced covid-19 infection by an average 86% (95% CI 79% to 91%). Secondary outcomes provided very-low or low certainty evidence. Low certainty evidence suggests that that there may be no benefit with ivermectin for ‘need for mechanical ventilation’, whereas effect estimates for ‘improvement’ and ‘deterioration’ favoured ivermectin use. Severe adverse events were rare and evidence of no difference was assessed as low to very low-certainty. Evidence on other secondary outcomes was very low certainty. Interpretation Low to moderate-certainty evidence suggests reductions in covid-19 deaths and infections may be possible by using ivermectin. Employing ivermectin early on may reduce the number of people progressing to severe disease. The apparent safety and low cost suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally.
... Ivermectin currently acts as a distinguished inhibitor of importin α/β1 protein complex, and in averting nuclear import, it also inhibits the 3CLpro protease, and thus, it probably halts the viral replication in the host [106][107][108][109]. However, it did not get FDA approval for the treatment of COVID-19 disease but had been employed for COVID-19 treatment in a number of countries where the rate of mortality was diminished after its application [110,111]. No appropriate data on phase III clinical trials are available regarding its benefits against COVID-19 [112], except for some data on Phase I clinical trials done in the U.K. by the Medicines & Healthcare Products Regulatory Agency [113]. ...
Article
COVID-19, a dreaded and highly contagious pandemic, is flagrantly known for its rapid prevalence across the world. Till date, none of the treatments are distinctly accessible for this life-threatening disease. Under the prevailing conditions of medical emergency, one creative strategy for the identification of novel and potential antiviral agents gaining momentum in research institutions and progressively being leveraged by pharmaceutical companies is target-based drug repositioning/repurposing. A continuous monitoring and recording of results offer an anticipation that this strategy may help to reveal new medications for viral infections. This review recapitulates the neoteric illation of COVID-19, its genomic dispensation, molecular evolution via phylogenetic assessment, drug targets, the most frequently worldwide used repurposed drugs and their therapeutic applications, and a recent update on vaccine management strategies. The available data from solidarity trials exposed that the treatment with several known drugs, viz. lopinavir-ritonavir, chloroquine, hydroxychloroquine, etc had displayed various antagonistic effects along with no impactful result in diminution of mortality rate. The drugs like remdesivir, favipiravir, and ribavirin proved to be quite safer therapeutic options for treatment against COVID-19. Similarly, dexamethasone, convalescent plasma therapy and oral administration of 2DG are expected to reduce the mortality rate of COVID-19 patients.
... Over 20 countries have adopted Ivermectin and many of these countries have COVID-19 case rates and death rates that are only a fraction of the U.S. rate. These include India [243], Mexico [244], and Peru [245]. ...
Article
Full-text available
Vaccines against COVID-19 have been available for about one year, but compliance with these vaccines has been less than expected. Vaccine hesitancy and refusal have limited vaccination rates, thus contributing to morbidity and mortality associated with COVID-19. This review explores the history of vaccines, beginning with their use in India over 3,500 years ago to prevent smallpox, and continuing through their current use to combat COVID-19. The past efforts of governments to compel individuals to get vaccinated are reviewed as well as the problems that resulted from such actions. Historical and contemporary factors that contribute to vaccine hesitancy are examined. One such factor is concern about the risks of the vaccines. Most adverse effects associated with the COVID-19 vaccines are mild. However, rare but serious adverse effects also occur including anaphylaxis, thrombosis, and myocarditis. Concerns about these potentially life-threatening complications contribute to vaccine hesitancy. The lack of an adequate system for reporting adverse events as well as the absence of an effective compensatory system to assist those who suffer untoward problems resulting from COVID-19 vaccines also contribute to vaccine hesitancy. Still another factor impeding vaccine compliance is lack of trust. This includes lack of trust in the vaccines, the pharmaceutical companies who manufacture the vaccines, the healthcare providers who recommend the vaccines, the governmental agencies who determine policies about the vaccines, and the media who report on the vaccines. The basis for mistrust in each of these areas is examined and includes a lack of transparency, ulterior financial motives, and suppression of alternative viewpoints. The effects of rumors and conspiracy theories on attitudes about vaccines are assessed as well. Finally, tactics utilized to increase vaccination rates are reviewed. These include education, persuasion, incentivization, and coercion. When education and persuasion fail, governments may turn to the use of coercive strategies, such as imposing vaccine mandates and implementing penalties and restrictions on those who fail to comply. The potential adverse consequences of these approaches are reviewed and include an unexpected decrease in vaccination rates, failure to protect individual autonomy, lack of informed consent associated with vaccinations, and polarization between the vaccinated and the unvaccinated leading to-vaccine tribalism.‖ Evidence demonstrating the efficacy of these approaches for improving vaccination compliance is found to be lacking. Thus, further research is recommended to find improved methods for improving vaccination rates as well as exploring alternative strategies for ending the COVID-19 pandemic, such as the concurrent use of effective antiviral treatments.
... The routine prophylactic administration of ivermectin in Peru starting from May 2020 was also associated with a reduction in mortality due to SARS-CoV-2 [43]. Hashim et al., in a randomized controlled study conducted on 70 COVID-19 patients also observed a reduction in recovery time and a reduction in mortality in severe patients treated with doxycycline and ivermectin [44]. ...
Article
Full-text available
Purpose of the study Currently no treatment has been proven to be efficacious for patients with early symptoms of COVID-19. Although most patients present mild or moderate symptoms, up to 5-10% may have a poor disease progression, so there is an urgent need for effective drugs, which can be administered even before the onset of severe symptoms, i.e. when the course of the disease is modifiable. Recently, promising results of several studies on oral ivermectin have been published, which has prompted us to conduct the present review of the scientific literature. Methods A narrative review has been carried out, focusing on the following four main topics: a) short-term efficacy in the treatment of the disease, b) long-term efficacy in the treatment of patients with post-acute symptoms of COVID-19, c) efficacy in the prophylaxis of the disease, and c) safety of ivermectin. Results The reviewed literature suggests that there seems to be sufficient evidence about the safety of oral ivermectin, as well as the efficacy of the drug in the early-treatment and the prophylaxis of COVID-19. Conclusions In the view of the available evidence, the Frontline COVID-19 Critical Care Alliance (FLCCC) recommends the use of oral ivermectin for both prophylaxis and early-treatment of COVID-19. Further well-designed studies should be conducted in order to explore the efficacy and safety of invermectin at low and high doses, following different dosing schedules, in both, the short and long-term treatment.
... In the beginning of October, Chamie published a preprint reviewing the epidemiological "real-world" evidence of the effect of ivermectin mass distribution in Peru on COVID-19 excess deaths in the population older than 60 years [126]. ...
Preprint
Full-text available
First part part of the timeline covering a period from April 2020 to March 2021 (this is an extended version of an earlier preprint written on March 24, 2021. Changes: Abstract, Introduction, April 26, September 25, December 7, February 9, March 15, from March 22 to March 31, Discussion) *** Other parts: Part 0: https://www.researchgate.net/publication/348077948 *** *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
... In the beginning of October, Chamie published a preprint reviewing the epidemiological "real-world" evidence of the effect of ivermectin mass distribution in Peru on COVID-19 excess deaths in the population older than 60 years. 115 The data was presented also on TrialSite News on October 5. 116 The article commented that "the Peruvian government approved the use of ivermectin by decree on May 8. Despite having received several requests to suspend it in September . . . the new Minister of Health ratified it. These measures have aroused much criticism among the scientific community. ...
Preprint
Full-text available
This is an outdated version of the first part of the timeline. Please see current versions *** Part 0: https://www.researchgate.net/publication/348077948 *** Part 1: https://doi.org/10.13140/RG.2.2.13705.36966 *** Part 2: https://doi.org/10.13140/RG.2.2.16973.36326 *** Part 3: https://doi.org/10.13140/RG.2.2.23081.72805 *** Part 4: https://doi.org/10.13140/RG.2.2.26000.53767 *** Part 5: https://doi.org/10.13140/RG.2.2.35015.16807 *** Additional notes (Feb-Apr 2022): https://doi.org/10.13140/RG.2.2.24356.55682 ***
Article
The global number of deaths due to COVID-19 is almost at the two million mark, with over 35 000 deaths in South Africa. Although there are hopes of a safe and effective vaccination programme, the increasing number of COVID-19 cases in the country is putting a significant strain on the healthcare system. Ivermectin, an antiparasitic drug, has been widely published on social media platforms and news outlets as a so-called miracle drug for the treatment of COVID-19. Ivermectin is not registered in SA as a drug for human use, but rather as a veterinary and agricultural product. Currently, from a small number of randomised controlled trials (RCTs), there does seem to be a signal of evidence for the use of ivermectin in the management of COVID-19. Pharmacists must, however, remain cognisant of their ethical responsibilities as well as the applicable regulations that prohibit the procurement and dispensing of any unregistered medicine.
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