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Atazanavir In Vitro vs COVID - A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19
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Recent data reported darunavir was not successful. Atazanavir might be effective in vitro stdy says yes. Although published study found kaletra not effective enough some hope regarding kaletra potential benefir persists because there were some benefits seen in study & the study was in very advanced COVID patients so perhaps kaletra might provide benefit in less advanced COVID or as prevention. With anecdotal reports that HIV+ do not seem to be contracting COVID at any higher rates vs HIV- 2 reasons why are theorized - 1 - immune suppression in HIV may prevent inflammatory cytokine storm response to COVID which seems to cause damage and 2 - perhaps HIV medications are protective, Truvada stdy is starting in Spain, some of raised perhaps integrse inhibitors play a role since so many if not most are on integrase today and hardly anyone on Is anymore. I do not think we have data on tegrase yet & CVID. Jules
Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
https://www.biorxiv.org/content/10.1101/2020.04.04.020925v2.full.pdf
ATV has been described to reach the lungs after intravenous administration......Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.....The HIV drug Kaletra did not show benefits in keeping patients alive, reducing the amount of virus in patients, or shortening their hospital stays, the researchers concluded in a New England Journal of Medicine article published on March 18. ......The potencies of LPV and LPV/RTV against CoV are from 10 to 8 μM, respectively32. Based on our data, ATV and ATV/RTV are at least 10 times more potent. The ATV and ATV/RTV in vitro potencies are comparable to other small molecule inhibitors of the SARS-CoV-2, such as remdesivir and CQ......We showed that ATV and ATV/RTV decreased IL-6 release in SARS-CoV-2-infected human primary monocytes.....Among the most promising anti-SARS-CoV-2 drugs, CQ, IFN-β and LPV displayed a higher toxic profile than ATV. Moreover, ATV and ATV/RTV have in vitro antiviral potencies comparable to CQ and remdesivir, which were superior to LPV/RTV. In summary, our study highlights a new option among clinically approved drugs that should be considered in ongoing clinical trials for an effective treatment for COVID-19.
Building on this continuous investigation, an unprecedented effort to run a global clinical trial, called SOLIDARITY, is ongoing under the auspicious of the World Health Organization (WHO) and the United Nations (UN)9. This mega trial has been putting forward lopinavir (LPV)/ritonavir (RTV), in combination or not with interferon-β (IFN-β), chloroquine (CQ) and remdesivir to treat COVID-199. LPV, RTV and remdesivir target viral enzymes, while the actions of CQ and IFN-β target host cells........he most successful antiviral drugs often directly target viral enzymes10. For CoVs, its major protease (Mpro) has been a promissing drug target for almost two decades, starting with early studies on 2002 SARS-CoV that showed this enzyme to be inhibited by LPV/RTV, inhibitors of HIV protease......In a combined therapy of LPV with RTV, LPV is included as the principle antiviral compound and RTV as an inhibitor cytochrome p450.......ATV alone or withRTV could inhibit viral replication in cell culture models of infection that also prevented the release of a cytokine storm-associated mediator.
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A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282
Our patient population was heterogeneous with regard to duration and severity of illness at enrollment.. In a post hoc subgroup analysis, the difference in mortality between the lopinavir-ritonavir group and the standard-care group was observed to be numerically greater among patients treated within 12 days after the onset of symptoms than among those treated later. The question of whether earlier lopinavir-ritonavir treatment in Covid-19 could have clinical benefit is an important one that requires further study.
The finding is consistent with studies showing that patients with SARS-CoV-2 viral pneumonia have progression in the second week of illness1 and with the time-to-treatment effects observed in previous antiviral studies in SARS20 and severe influenza.21-23 In addition, we found that the numbers of lopinavir-ritonavir recipients who had serious complications (acute kidney injury and secondary infections) or requiring noninvasive or invasive mechanical ventilation for respiratory failure were fewer than in those not receiving treatment. These observations are hypothesis-generating and require additional studies to determine whether lopinavir-ritonavir treatment given at a certain stage of illness can reduce some complications in Covid-19.
Whether combining lopinavir-ritonavir with other antiviral agents, as has been done in SARS5,20 and is being studied in MERS-CoV,15 might enhance antiviral effects and improve clinical outcomes remains to be determined.
Patients assigned to lopinavir-ritonavir did not have a time to clinical improvement different from that of patients assigned to standard care alone in the intention-to-treat population (median, 16 day vs. 16 days; hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.85; P=0.09) (Figure 2).
In the intention-to-treat population, lopinavir-ritonavir treatment within 12 days after the onset of symptoms was not found to be associated with a shorter time to clinical improvement (hazard ratio, 1.25; 95% CI, 0.77 to 2.05); similar results were found regarding later treatment with lopinavir-ritonavir (hazard ratio, 1.30; 95% CI, 0.84 to 1.99) (Fig. S2A and S2B).
Patients in the lopinavir-ritonavir group had a shorter stay in the intensive care unit (ICU) than those in the standard-care group (median, 6 days vs. 11 days; difference, -5 days; 95% CI, -9 to 0), and the duration from randomization to hospital discharge was numerically shorter (median, 12 days vs. 14 days; difference, 1 day; 95% CI, 0 to 3). In addition, the percentage of patients with clinical improvement at day 14 was higher in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%; difference, 15.5 percentage points; 95% CI, 2.2 to 28.8) (Fig. S5). There were no significant differences for other outcomes such as duration of oxygen therapy, duration of hospitalization, and time from randomization to death.
A total of 69 patients (35%) who had a diagnostic respiratory tract sample that was positive on RT-PCR had a negative RT-PCR result on the throat swab taken after consent. The mean (±SD) baseline viral RNA loads in the throat swabs taken after consent were slightly higher in the lopinavir-ritonavir group than in the standard-care group at randomization (4.4±2.0 log10 copies per milliliter vs. 3.7±2.1) (Table 2). The viral RNA loads over time did not differ between the lopinavir-ritonavir recipients and those receiving standard care (Figure 3), including analysis according to duration of illness (Fig. S6).
The percentage of patients with detectable viral RNA for SARS-CoV-2 was similar in the lopinavir-ritonavir group and the standard-care group on any sampling day (day 5, 34.5% vs. 32.9%; day 10, 50.0% vs. 48.6%; day 14, 55.2% vs. 57.1%; day 21, 58.6% vs. 58.6%; and day 28, 60.3% vs. 58.6%) (Table S2).
We did not find that adding lopinavir-ritonavir treatment reduced viral RNA loads or duration of viral RNA detectability as compared with standard supportive care alone. SARS-CoV-2 RNA was still detected in 40.7% of the patients in the lopinavir-ritonavir group at end of the trial (day 28). A recent report showed that the median duration of viral shedding in Covid-19 was 20 days in patients with severe illness and could be as long as 37 days.24 Neither that study nor the current one found evidence that lopinavir-ritonavir exerted a significant antiviral effect. The reasons for the apparent lack of antiviral effect are uncertain, but the sampling methods used in the current trial were most likely suboptimal. Samples were taken only intermittently (on days 1, 5, 10, 14, 21, and 28), and more frequent sampling in the first 5 days could have provided more detailed characterization of viral load kinetics in the two groups over this critical period. In addition, previous studies have shown that throat-swab specimens have lower viral loads than nasopharyngeal samples,25 and importantly, we were unable to do sampling of lower respiratory tract secretions. Of note, depending on cell type used, the 50% effective concentrations (EC50) of lopinavir in vitro for SARS-CoV has ranged from 4.0 to 10.7 μg per milliliter,5,6,8 although other studies reported that lopinavir was inactive26 or that higher concentrations (25 μg per milliliter) were required for inhibition.7 For MERS-CoV, the EC50 values have ranged from 5 to approximately 7 μg per milliliter).1,8,13 Both the mean peak (9.6 μg per milliliter) and trough (5.5 μg per milliliter) serum concentrations of lopinavir in adults just approach these concentrations. Whether the EC50 value is an adequate threshold and whether unbound lopinavir concentrations in human plasma are sufficient for inhibition of SARS-CoV-2 are questionable.1
Nearly 14% of lopinavir-ritonavir recipients were unable to complete the full 14-day course of administration. This was due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse events, both acute gastritis. Two recipients had self-limited skin eruptions. Such side effects, including the risks of hepatic injury, pancreatitis, more severe cutaneous eruptions, and QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are well documented with this drug combination. The side-effect profile observed in the current trial arouses concern about the use of higher or more prolonged lopinavir-ritonavir dose regimens in efforts to improve outcomes.
Our trial has several limitations. In particular, the trial was not blinded, so it is possible that knowledge of the treatment assignment might have influenced clinical decision-making that could have affected the ordinal scale measurements we used. We will continue to follow these patients to evaluate their long-term prognosis. The characteristics of the patients at baseline were generally balanced across the two groups, but the somewhat higher throat viral loads in the lopinavir-ritonavir group raise the possibility that this group had more viral replication. Although we did not observe differences between groups in the frequency of use of concurrent pharmacologic interventions, such as glucocorticoids, this might have been another confounder. In addition, approximately 45% and 40% of the patients in lopinavir-ritonavir group had positive RNA detection by throat swabs on day 14 and day 28, respectively, but we do not know if infectious virus was still present, since we did not attempt virus isolation or assess the possible emergence of SARS-CoV-2 variants with reduced susceptibility to lopinavir. Finally, we do not have data on the lopinavir exposure levels in these seriously and often critically ill patients.
In conclusion, we found that lopinavir-ritonavir treatment did not significantly accelerate clinical improvement, reduce mortality, or diminish throat viral RNA detectability in patients with serious Covid-19. These early data should inform future studies to assess this and other medication in the treatment of infection with SARS-CoV-2. Whether combining lopinavir-ritonavir with other antiviral agents, as has been done in SARS5,20 and is being studied in MERS-CoV,15 might enhance antiviral effects and improve clinical outcomes remains to be determined.
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