Coronavirus Treatment- HIV Protease Inhibitors
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No antiviral treatment for coronavirus infection has been proven to be effective. In a historical control study, the combination of lopinavir and ritonavir among SARS-CoV patients was associated with substantial clinical benefit (fewer adverse clinical outcomes). Arabi and colleagues initiated a placebo-controlled trial of interferon beta-1b, lopinavir, and ritonavir among patients with MERS infection in Saudi Arabia. Preclinical evidence showed the potent efficacy of remdesivir (a broad-spectrum antiviral nucleotide prodrug) to treat MERS-CoV and SARS-CoV infections. As 2019-nCoV is an emerging virus, an effective treatment has not been developed for disease resulting from this virus. Since the combination of lopinavir and ritonavir was already available in the designated hospital, a randomised controlled trial has been initiated quickly to assess the efficacy and safety of combined use of lopinavir and ritonavir in patients hospitalised with 2019-nCoV infection.
China repurposes AbbVie HIV drug as Big Pharma rallies to combat deadly coronavirus
There aren't any drugs or vaccines approved specifically for the new virus. No antiviral treatment has proven effective against coronaviruses. But one hospital in Wuhan has started a clinical trial using a combination of two drugs that had been tested on MERS patients in Saudi Arabia. The therapy, sold under the brand name Kaletra in the U.S., is normally used to treat HIV patients and belongs to a class of drugs known as protease inhibitors, which block a key enzyme that helps viruses replicate. Re-searchers are also investigating other antivirals. In addition, a few vaccine makers are developing products targeting the virus.
On Sunday, a Chinese national health program recommended the use of a treatment from AbbVie, which the company sells under the brand names Kaletra and Aluvia, according to Beijing's Health Commission.
The therapy, first approved two decades ago to treat HIV, combines two antiviral agents. It belongs to a class of drugs known as protease inhibitors, which block a key enzyme that helps viruses replicate.
AbbVie, which is based in the Chicago suburbs, donated about $2 million worth of Kaletra doses as an "experimental option" in response to a request by Chinese health authorities, a company spokeswoman said. She added that China, not AbbVie, is leading testing of the therapy for treating coronavirus.
A hospital in Wuhan is conducting a randomized clinical trial to assess whether Kaletra works against the new illness, researchers said in an article published Friday in The Lancet medical journal.
Researchers previously have found the drug to be effective in treating another coronavirus: A combination of the two drugs that make up Kaletra, lopinavir and ritonavir, administered to patients with SARS showed a "substantial clinical benefit," or fewer adverse clinical outcomes, according to a 2004 study published in the Thorax medical journal.
Johnson & Johnson agreed to a request over the weekend by Chinese health authorities to ship its HIV drug Prezcobix for potential treatment of coronavirus infection, Chief Scientific Officer Paul Stoffels said in an interview.
The therapy, which is also a protease inhibitor combining two antiviral agents, should arrive by Tuesday, he said.
"Industry can take different steps to combating this epidemic as fast as possible," Dr. Stoffels said. Studying Prezcobix in patients who test positive for the coronavirus wouldn't harm them, he said, and could help authorities find a treatment that works.
Dr. Stoffels said J&J is also reviewing its library of compounds, including those currently in laboratories, that could potentially provide other help to patients.
Merck & Co. assigned a team of scientists to assess whether any of the company's internal assets might be effective against the Wuhan coronavirus, a spokesman said. Merck makes the only Ebola vaccine that has been approved by U.S. and European health authorities.
Gilead, of Foster City, Calif., is in talks with researchers and clinicians in the U.S. and China about using its experimental antiviral therapy, remdesivir, the company said. Remdesivir isn't licensed or approved inside or outside the U.S.
Gilead said remdesivir has been active against other coronaviruses in lab and animal studies. The same drug has reduced the severity of Ebola in human patients, though by a lesser degree than two other therapies for the infectious disease.
Remdesivir also has been shown to lessen lung disease from Middle East respiratory syndrome, a coronavirus known as MERS, in mice, according to a paper published earlier this month in Nature Communications.
In addition to efforts at repurposing existing antiviral treatments, several drugmakers and some academic researchers are also racing to develop a vaccine to prevent coronavirus infections.
J&J will also try to develop a vaccine, using the same technology applied to its Ebola vaccine, currently used in Africa, Dr. Stoffels said. It could be tested in humans in eight to 12 months.
To battle the coronavirus emergency, Chinese government and medical experts are taking some unconventional measures, including publicly backing off-label use of a Big Pharma drug.
AbbVie's fixed-dose HIV drug Kaletra-also known as Aluvia, is now recommended as a treatment for pneumonia caused by the new coronavirus known as 2019-nCoV, China's National Health Commission says in its updated clinical guidance.
In response, the Illinois pharma is donating CNY 10 million (about $1.5 million) worth of the drug to help contain the virus, its China branch said (Chinese) Friday.
Kaletra's two antiretroviral components, lopinavir and ritonavir, are protease inhibitors designed to block HIV viral replication. One hypothesis holds that the drugs could do the same with 2019-nCoV, which is believed to have originated from the Chinese city of Wuhan. Although not approved to treat any coronavirus anywhere, it has shown efficacy in at least one case in the current outbreak in China.
Wang Guangfa, the leader of Peking University First Hospital's pulmonary and critical care medicine department, contracted the virus as a member of a national expert team dispatched to Wuhan. Kaletra killed his disease, Wang told state-run China News Service in a report (Chinese) on Thursday.
It's worth noting that this isn't the first time Kaletra has worked against a coronavirus. In a historical control study in 2004, "the combination of lopinavir and ritonavir among SARS-CoV patients was associated with substantial clinical benefit (fewer adverse clinical outcomes)," Chinese researchers noted in a newly published The Lancet study, which describes the clinical features of the first 41 patients infected with 2019-nCoV.
However, the study authors and the government both cautioned that there are no treatments confirmed to be effective against the new pathogen.
SARS, or severe acute respiratory syndrome, is also caused by a coronavirus, and the older pathogen bears much resemblance to the newly emerged one. SARS hit China hard during a 2002-2003 epidemic, killing about 700 in the country alone. As of Sunday, 2019-nCoV has led to 2,744 confirmed infections in all parts of China and killed 80 people, according to Chinese authorities.
China has adopted various measures to contain the virus, including putting Wuhan-population 11 million-on complete quarantine, implementing the highest level of public health response across the country, and extending the Chinese New Year holiday to avoid large-scale migration that could contribute to disease spread. Drugmakers are stepping up their efforts as well.
Antiviral specialist Gilead Sciences is considering repurposing its failed Ebola drug remdesivir for the virus. Moderna Therapeutics is working with the NIH's National Institute of Allergy and Infectious Diseases on the development of an mRNA vaccine, with some funding from the Coalition for Epidemic Preparedness Innovations (CEPI). Johnson & Johnson also just unveiled a plan to expedite work on a vaccine. Pennsylvania-based Inovio Pharmaceuticals secured $9 million CEPI funding for its own program.
In China, besides AbbVie's Kaletra contribution, Bayer on Sunday also said it would donate CNY 6.5 million worth of medicines and another CNY 4.5 million in cash to help purchase medical protection products for Wuhan.
Local operations of Roche, AstraZeneca, Pfizer, Eli Lilly, Sanofi, Novo Nordisk, J&J, Allergan, GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Fresenius Kabi and Takeda have all announced plans to donate money or products in the million-yuan range each to support the cause.
Since the cause was unknown at the onset of these emerging infections, the diagnosis of pneumonia of unknown cause in Wuhan was based on clinical characteristics, chest imaging, and the ruling out of common bacterial and viral pathogens that cause pneumonia. Suspected patients were isolated using airborne precautions in the designated hospital, Jin Yin-tan Hospital (Wuhan, China), and fit-tested N95 masks and airborne precautions for aerosol-generating procedures were taken.
Local centres for disease control and prevention collected respiratory, blood, and faeces specimens, then shipped them to designated authoritative laboratories to detect the pathogen (NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mrieux Laboratory, Beijing, China). A novel coronavirus, which was named 2019-nCoV, was isolated then from lower respiratory tract specimen and a diagnostic test for this virus was developed soon after that.
Of 59 suspected cases, 41 patients were confirmed to be infected with 2019-nCoV. The presence of 2019-nCoV in respiratory specimens was detected by next-generation sequencing or real-time RT-PCR methods.
Initial investigations included a complete blood count, coagulation profile, and serum biochemical test (including renal and liver function, creatine kinase, lactate dehydrogenase, and electrolytes). Respiratory specimens, including nasal and pharyngeal swabs, bronchoalveolar lavage fluid, sputum, or bronchial aspirates were tested for common viruses, including influenza, avian influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, SARS-CoV and MERS-CoV using real-time RT-PCR assays approved by the China Food and Drug Administration. Routine bacterial and fungal examinations were also performed.
Given the emergence of the 2019-nCoV pneumonia cases during the influenza season, antibiotics (orally and intravenously) and oseltamivir (orally 75 mg twice daily) were empirically administered. Corticosteroid therapy (methylprednisolone 40-120 mg per day) was given as a combined regimen if severe community-acquired pneumonia was diagnosed by physicians at the designated hospital. Oxygen support (eg, nasal cannula and invasive mechanical ventilation) was administered to patients according to the severity of hypoxaemia. Repeated tests for 2019-nCoV were done in patients confirmed to have 2019-nCoV infection to show viral clearance before hospital discharge or discontinuation of isolation.
By Jan 2, 2020, 41 admitted hospital patients were identified as laboratory-confirmed 2019-nCoV infection in Wuhan. 20 [49%]) of the 2019-nCoV-infected patients were aged 25-49 years, and 14 (34%) were aged 50-64 years (figure 1A). The median age of the patients was 49⋅0 years (IQR 41⋅0-58⋅0; table 1). In our cohort of the first 41 patients as of Jan 2, no children or adolescents were infected. Of the 41 patients, 13 (32%) were admitted to the ICU because they required high-flow nasal cannula or higher-level oxygen support measures to correct hypoxaemia. Most of the infected patients were men (30 [73%]); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]).
The most common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38; table 1). More than half of patients (22 [55%] of 40) developed dyspnoea. The median duration from illness onset to dyspnoea was 8⋅0 days (IQR 5⋅0-13⋅0). The median time from onset of symptoms to first hospital admission was 7⋅0 days (4⋅0-8⋅0), to shortness of breath was 8⋅0 days (5⋅0-13⋅0), to ARDS was 9⋅0 days (8⋅0-14⋅0), to mechanical ventilation was 10⋅5 days (7⋅0-14⋅0), and to ICU admission was 10⋅5 days (8⋅0-17⋅0; figure 2).
The blood counts of patients on admission showed leucopenia (white blood cell count less than 4 x 109/L; ten [25%] of 40 patients) and lymphopenia (lymphocyte count <1⋅0 x 109/L; 26 [63%] patients; table 2). Prothrombin time and D-dimer level on admission were higher in ICU patients (median prothrombin time 12⋅2 s [IQR 11⋅2-13⋅4]; median D-dimer level 2⋅4 mg/L [0⋅6-14⋅4]) than non-ICU patients (median prothrombin time 10⋅7 s [9⋅8-12⋅1], p=0⋅012; median D-dimer level 0⋅5 mg/L [0⋅3-0⋅8], p=0⋅0042). Levels of aspartate aminotransferase were increased in 15 (37%) of 41 patients, including eight (62%) of 13 ICU patients and seven (25%) of 28 non-ICU patients. Hypersensitive troponin I (hs-cTnI) was increased substantially in five patients, in whom the diagnosis of virus-related cardiac injury was made.
Most patients had normal serum levels of procalcitonin on admission (procalcitonin <0⋅1 ng/mL; 27 [69%] patients; table 2). Four ICU patients developed secondary infections. Three of the four patients with secondary infection had procalcitonin greater than 0⋅5 ng/mL (0⋅69 ng/mL, 1⋅46 ng/mL, and 6⋅48 ng/mL).
On admission, abnormalities in chest CT images were detected among all patients. Of the 41 patients, 40 (98%) had bilateral involvement (table 2). The typical findings of chest CT images of ICU patients on admission were bilateral multiple lobular and subsegmental areas of consolidation (figure 3A). The representative chest CT findings of non-ICU patients showed bilateral ground-glass opacity and subsegmental areas of consolidation (figure 3B). Later chest CT images showed bilateral ground-glass opacity, whereas the consolidation had been resolved (figure 3C).
Initial plasma IL1B, IL1RA, IL7, IL8, IL9, IL10, basic FGF, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1A, MIP1B, PDGF, TNFα, and VEGF concentrations were higher in both ICU patients and non-ICU patients than in healthy adults (appendix pp 6-7). Plasma levels of IL5, IL12p70, IL15, Eotaxin, and RANTES were similar between healthy adults and patients infected with 2019-nCoV. Further comparison between ICU and non-ICU patients showed that plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα were higher in ICU patients than non-ICU patients.
All patients had pneumonia. Common complications included ARDS (12 [29%] of 41 patients), followed by RNAaemia (six [15%] patients), acute cardiac injury (five [12%] patients), and secondary infection (four [10%] patients; table 3). Invasive mechanical ventilation was required in four (10%) patients, with two of them (5%) had refractory hypoxaemia and received extracorporeal membrane oxygenation as salvage therapy. All patients were administered with empirical antibiotic treatment, and 38 (93%) patients received antiviral therapy (oseltamivir). Additionally, nine (22%) patients were given systematic corticosteroids. A comparison of clinical features between patients who received and did not receive systematic corticosteroids is in the appendix (pp 1-5).
As of Jan 22, 2020, 28 (68%) of 41 patients have been discharged and six (15%) patients have died. Fitness for discharge was based on abatement of fever for at least 10 days, with improvement of chest radiographic evidence and viral clearance in respiratory samples from upper respiratory tract.