The Lungs Before and After COVID-19 Pneumonia
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A 69-year-old woman was admitted to our Emergency Department with cough and dyspnea.Laboratory investigations showed increased white blood cell count (10,500 per μL), and C-reactive protein levels (124 mg/dL).Chest X-ray (Figure 1A) showed findings consistent with bilateral interstitial pneumonia; COVID-19 was detected in a throat swab sample by RT-PCR.From day one, the patient suffered from a type I respiratory failure requiring supplemental oxygen through a Venturi mask, FiO 2 up to 60%.She was treated with lopinavir/ritonavir and hydroxychloroquine; because of the persistent severe conditions (Figure 1B), tocilizumab was added on day 14.Two days later, after improvement in respiratory exchange, the oxygen therapy was suspended.A slow progressive improvement occurred (Figure 1C), and on days 30 and 31, RT-PCR was negative.On day 32, the patient underwent an unenhanced chest computed tomography (CT), showing diffuse lung architectural distortion, with reticular interstitial pattern, peripheral honeycombing, and bronchial wall thickening.Images of a previous chest CT performed by the patient a year ago are available, showing no significant abnormalities.The dramatic pulmonary changes (Figure 2A and B) make us question the possible long-term consequences of COVID-19 pneumonia.Keywords:
Honeycombing
Hydroxychloroquine
Nasal cannula
Oxygen therapy
Ritonavir
Lopinavir
Thirty-four patients treated concomitantly with lopinavir/ritonavir and rifampicin were evaluated. Overall, only 15% used the recommended increased dose of lopinavir/ritonavir. Of patients on a nonadjusted dose of lopinavir/ritonavir, 67% had a subtherapeutic lopinavir plasma concentration and 38% had a detectable viral load. Forty percent of patients on an increased dose of lopinavir/ritonavir prematurely stopped the drug combination because of adverse events. Combined use of lopinavir/ritonavir and rifampicin is challenging as it implies balancing between suboptimal efficacy and toxicity.
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Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.
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To assess the most frequent resistance-associated mutations (RAMs) to lopinavir/ritonavir in a cohort of patients attended in daily practice.We retrospectively identified 195 multitreated subjects with virological failure. Patients were classified as follows: (i) 71 (36.4%) never received lopinavir/ritonavir (lopinavir/ritonavir naive); (ii) 75 (38.5%) had previously failed on lopinavir/ritonavir; and (iii) 49 (25.1%) were on lopinavir/ritonavir at failure. RAM patterns were assessed. Medians, IQRs, percentages, Kruskal-Wallis, χ(2) or Fisher's exact test, and multinomial logistic regression were used whenever appropriate.L10I/F, K20R, L24I, L33F, M36I, M46I/L, I47V, G48V, F53L, I54V, A71V, G73S, V82A, I84V and L90M (all with P ≤ 0.037) were protease RAMs overexpressed in patients with lopinavir/ritonavir failure. L10I, M36I, M46I, I54V, L63P, A71V, V82A, I84V and L90M were the most common in lopinavir/ritonavir-naive patients. Other IAS-USA RAMs for lopinavir/ritonavir (L10R/V, K20M, V32I, I47A, I50V, I54L/A/M/T/S, A71T, L76V and V82F/T/S) were not associated with previous or current failure to lopinavir/ritonavir. Lopinavir/ritonavir failure was associated with the number of protease RAMs (OR = 1.146, 95% CI = 1.287, 1.626), higher exposure to protease inhibitors, and the presence of E44D, L33F, I54V and I84V.In multitreated patients with previous or current lopinavir/ritonavir failure, some protease mutations are selected at significantly greater rates. L10I, M36I, I54V, L63P, A71V, V82A and L90M were found in >50% of cases. Thus, their presence should be expected when genotypic testing results are not available. The number of protease RAMs and higher prior exposures to protease inhibitors were significantly associated with lopinavir/ritonavir failure.
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OBJECTIVE:To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of lopinavir/ritonavir (Kaletra, Abbott Laboratories).DATA SOURCES:English-language MEDLINE and AIDSline searches were performed (1966–July 2001) using lopinavir, ABT-378, and Kaletra as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Abbott Laboratories provided additional published and unpublished information.DATA EXTRACTION:All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. In vitro and preclinical studies were included as well as Phase II and III clinical trials.DATA SYNTHESIS:Lopinavir/ritonavir is a fixed-dose protease inhibitor (PI) combination used for the treatment of HIV-1 infection. Lopinavir, the active component of this combination, is extensively metabolized by CYP3A4 and produces low systemic concentrations when used alone. Ritonavir potently inhibits CYP3A4 and is used to enhance the systemic exposure of lopinavir. This combination results in lopinavir concentrations that greatly exceed those necessary in vitro to inhibit both wild-type and PI-resistant HIV isolates. In clinical trials with antiretroviral naïve and experienced patients, lopinavir/ritonavir was effective at suppressing HIV-RNA and increasing CD4+ T cell counts. Compared with other PIs, lopinavir/ritonavir may have advantages in the areas of pharmacokinetics, efficacy, and resistance. Toxicity, drug interactions, and medication adherence are important considerations surrounding its clinical use.CONCLUSIONS:Lopinavir/ritonavir is an effective option for the treatment of HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as a component of initial therapy or salvage therapy; future studies will better define its place in therapy.
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OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, and clinical use of lopinavir/ritonavir (Kaletra, Abbott Laboratories). DATA SOURCES: English-language MEDLINE and AIDSline searches were performed (1966–July 2001) using lopinavir, ABT-378, and Kaletra as key words. Abstracts from infectious diseases and HIV scientific meetings were identified. Abbott Laboratories provided additional published and unpublished information. DATA EXTRACTION: All publications, meeting abstracts, and unpublished information were reviewed and relevant items included. In vitro and preclinical studies were included as well as Phase II and III clinical trials. DATA SYNTHESIS: Lopinavir/ritonavir is a fixed-dose protease inhibitor (PI) combination used for the treatment of HIV-1 infection. Lopinavir, the active component of this combination, is extensively metabolized by CYP3A4 and produces low systemic concentrations when used alone. Ritonavir potently inhibits CYP3A4 and is used to enhance the systemic exposure of lopinavir. This combination results in lopinavir concentrations that greatly exceed those necessary in vitro to inhibit both wild-type and PI-resistant HIV isolates. In clinical trials with antiretroviral naïve and experienced patients, lopinavir/ritonavir was effective at suppressing HIV-RNA and increasing CD4+ T cell counts. Compared with other PIs, lopinavir/ritonavir may have advantages in the areas of pharmacokinetics, efficacy, and resistance. Toxicity, drug interactions, and medication adherence are important considerations surrounding its clinical use. CONCLUSIONS: Lopinavir/ritonavir is an effective option for the treatment of HIV-1-infected individuals when used in combination with other antiretroviral agents. It may be used as a component of initial therapy or salvage therapy; future studies will better define its place in therapy.
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To assess the virologic response rates of atazanavir/ritonavir and lopinavir/ritonavir based on baseline genotype and phenotype.Resistance analyses were performed on a Bristol-Myers Squibb-sponsored study comparing the safety and efficacy of atazanavir/ritonavir to lopinavir/ritonavir in treatment-experienced subjects at 48 weeks. Analyses evaluated virologic response based on the presence of baseline primary protease inhibitor mutations and baseline susceptibility.Less than 30% of atazanavir/ritonavir-treated patients were responders if substitutions at positions M46, G73, I84 or L90 were present in their HIV at baseline. In comparison, lopinavir/ritonavir response rates were less than 30% when protease substitutions at M46, I54, or I84 were present at baseline. The response rates were similar between atazanavir/ritonavir and lopinavir/ritonavir-treated subjects with zero to four baseline protease inhibitor mutations, but response rates were reduced if five or more baseline mutations were present: 0% for atazanavir/ritonavir compared with 28% for lopinavir/ritonavir. Baseline phenotype results showed that response rates were similar between atazanavir/ritonavir and lopinavir/ritonavir if shifts in susceptibility were zero to five, but response rates were lower if shifts were greater than five; 11% for atazanavir/ritonavir compared with 27% for lopinavir/ritonavir.Both type and number of baseline protease inhibitor mutations affected virologic response to atazanavir/ritonavir and lopinavir/ritonavir in treatment-experienced subjects. In addition, baseline phenotypic susceptibility could differentiate virologic response rates to the two drugs. These resistance analyses provide information on the likelihood of a virologic response to antiretroviral drugs based on baseline genotypic and phenotypic data, which is valuable to physicians and patients when choosing antiretroviral regimens.
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Background: Yindan Jiedu Granules (YDJDG) have been newly prescribed as a Chinese herbal formula. This study aimed to compare the efficacy of YDJDG and lopinavir-ritonavir in the treatment of coronavirus disease 2019 (COVID-19). Methods: Overall, 131 patients with COVID-19 were included in this study. In addition to standard care, 60 of these patients received YDJDG (YDJDG group) and 71 received lopinavir-ritonavir (lopinavir-ritonavir group). Propensity score matching (PSM) was used to match the characteristics of individuals in the two groups, while the Kaplan-Meier method was used to compare the proportion recovery observed. Results: Cox analysis revealed that YDJDG and CD4 ≥ 660 cells/µL were independent predictive factors of proportion recovery. At baseline, disease types differed between the YDJDG and lopinavir-ritonavir treatment groups. Furthermore, no significant adverse effects or toxicities relevant to YDJDG were observed. The median recovery time was 21 days in the YDJDG group and 27 days in the lopinavir-ritonavir group. After PSM (1:1), 50 patient pairs, YDJDG vs. lopinavir-ritonavir, were analyzed. In the YDJDG group, the proportion of recovered patients was remarkably higher than that observed in the lopinavir-ritonavir group ( p = 0.0013), especially for those presenting mild/moderate disease type and CD4 < 660 cells/µL. In the YDJDG group, the mean duration of fever and pulmonary exudative lesions was significantly shorter than that observed in the lopinavir-ritonavir group ( p = 0.0180 and p = 0.0028, respectively). Conclusion: YDJDG reveals the potential to hasten the recovery period in COVID-19 patients with mild/moderate disease type or CD4 < 660 cells/µL by shortening the mean duration of fever and pulmonary exudative lesions.
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ABSTRACT COVID-19 has caused over 900,000 deaths worldwide as of September 2020, and effective medicines are urgently needed. Lopinavir was identified as an inhibitor of the HIV protease, and a lopinavir-ritonavir combination therapy was reported to be beneficial for the treatment of SARS and MERS. However, recent clinical tests could not prove that lopinavir-ritonavir therapy was an effective treatment for COVID-19. In this report, we examined the effect of lopinavir and ritonavir to the activity of the purified main protease (Mpro) protein of SARS- CoV-2, the causative virus of COVID-19. Unexpectedly, lopinavir and ritonavir did not inhibit Mpro activity. These results will aid the drug candidate selection for ongoing and future COVID-19 clinical trials.
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The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 µg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.
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The objective of this study was to determine the influence of a 2-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil.The study was conducted as an open label, single-sequence pharmacokinetic study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a Student t test after a single 600-mg dose was administered to healthy volunteers before and after 2 weeks of lopinavir-ritonavir (400/100 mg) twice daily.Fifteen healthy volunteers (eight males) completed the study. All study drugs were generally well tolerated and no subjects withdrew participation. The geometric mean ratio (90% confidence interval) for gemfibrozil area under the plasma concentration-time curve after 14 days of lopinavir-ritonavir compared with baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil area under the plasma concentration-time curve after lopinavir-ritonavir (range, -6% to -74%). The geometric mean ratios for gemfibrozil apparent oral clearance and maximum concentration were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P < 0.0001 and 0.01, respectively). Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60).Lopinavir-ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction.
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