LitCovid-sentences  

PMC:7696151 / 7084-41349 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T61 0-4 Sentence denotes 2.2.
T62 5-44 Sentence denotes Hydroxychloroquine and Viral Infections
T63 45-153 Sentence denotes HCQ has been used mainly as an antimalarial drug, but it has also proven effective against viral infections.
T64 154-342 Sentence denotes HCQ demonstrated its antiviral efficacy in inhibiting the endosomal-lysosomal acidification, which is essential for the entry, replication, and infection process of different viruses [12].
T65 343-474 Sentence denotes In particular, HCQ-induced alkalinization processes cause the expansion and vacuolization of lysosomes, inhibiting their functions.
T66 475-644 Sentence denotes This activity can reduce post-transcriptional protein modification, enzyme release, receptor recycling, activation of cell signaling pathways, and cell membranes repair.
T67 645-700 Sentence denotes As a result, there is the prevention of cell infection.
T68 701-803 Sentence denotes Further, HCQ antiviral activity is also related to its anti-inflammatory and immunomodulatory effects.
T69 804-1079 Sentence denotes Different studies have, indeed, demonstrated that viral diseases are caused by a direct viral infection of susceptible cells and also by an impact on the immune response with consequent uncontrolled release of pro-inflammatory chemokines, cytokines, and other mediators [13].
T70 1080-1249 Sentence denotes The most studied antiviral activity of HCQ is that exerted against HIV; however, the current spread of the Coronavirus infection has brought attention back to this drug.
T71 1250-1497 Sentence denotes In this systematic review, clinical and in vivo studies evaluating HCQ antiviral activity against the Human Immunodeficiency Virus (HIV), Chikungunya Virus (CHIKV), Flavivirus, and Coronavirus have been analyzed (Figure 3B, Figure 5, and Table 1).
T72 1499-1505 Sentence denotes 2.2.1.
T73 1506-1511 Sentence denotes HIV-1
T74 1512-1627 Sentence denotes HIV is part of the genus Lentivirus, of the Retroviridae family, and it is divided into two lines: HIV-1 and HIV-2.
T75 1628-1727 Sentence denotes The most virulent and infectious is HIV-1, since it causes most of the HIV infections in the world.
T76 1728-1867 Sentence denotes The target cells of HIV are those rich in CD4 receptors, such as some lymphocytes called CD4+, which play a crucial role in human immunity.
T77 1868-1998 Sentence denotes Indeed, these lymphocytes activate different immune system cells depending on the type of unwanted host they come in contact with.
T78 1999-2110 Sentence denotes It seems that acute HIV infection is highly linked to a rapid depletion of CD4+ T cells in gut lymphoid tissue.
T79 2111-2283 Sentence denotes This event is related to an alteration of the intestinal mucosa integrity, resulting in bloodstream translocation of microbial products like lipopolysaccharides (LPS) [42].
T80 2284-2461 Sentence denotes It has been hypothesized that LPS, through the binding and activation of Toll-like receptor 4 (TLR-4), is responsible for the immune system activation observed in HIV infection.
T81 2462-2676 Sentence denotes Although the real HCQ mechanism of action has not been well assessed, it seems that the anti-HIV effects are highly linked to the post-translational modification of glycoprotein 120 (gp120) in monocyte and T cells.
T82 2677-2799 Sentence denotes Consequently, there was a modification of gp120 immunogenic properties and a reduction of new virions infectivity [15,16].
T83 2800-2929 Sentence denotes The first randomized, double-blind, placebo-controlled clinical trial about the anti-HIV-1 activity of HCQ was published in 1995.
T84 2930-3041 Sentence denotes In this study, 40 asymptomatic HIV-infected patients received either 800 mg/day HCQ or placebo for eight weeks.
T85 3042-3231 Sentence denotes All patients treated with antiretroviral therapy (HAART = zidovudine (ZDV), 2′,3′-dideoxyinosine, or 2′,3′-dideoxycytidine) and stopped taking it four weeks before the clinical trial start.
T86 3232-3352 Sentence denotes Unlike placebo, at the eighth week, HCQ displayed a reduction in HIV-1 RNA total plasma levels in 12 out of 19 patients.
T87 3353-3565 Sentence denotes Furthermore, the percentage of CD4+ T cells decreased significantly in the placebo group and remained stable during the treatment with HCQ, indicating a probable stabilization of immune function in the HCQ group.
T88 3566-3666 Sentence denotes HCQ administration also induced a decrease in serum interleukin 6 (IL-6) and immunoglobulin G (IgG).
T89 3667-3741 Sentence denotes However, no significant changes were found in the IgA and IgM levels [17].
T90 3742-3957 Sentence denotes The anti-HIV-1 effect of HCQ was also compared with that of ZDV, a nucleoside reverse transcriptase inhibitor, in a randomized, placebo-controlled clinical trial conducted on 72 HIV-l-infected asymptomatic patients.
T91 3958-4053 Sentence denotes All subjects were treated for 16 weeks with 800 mg/day HCQ (n = 35) or 500 mg/day ZDV (n = 37).
T92 4054-4176 Sentence denotes As in the previous study, patients who had received HAART stopped taking it four weeks before the clinical trial’s outset.
T93 4177-4377 Sentence denotes After 16 weeks, total plasma HIV-1 RNA levels were reduced in both the ZDV group and HCQ group, although the extent of anti-HIV-l activity in HCQ patients was lower than that observed in ZDV subjects.
T94 4378-4542 Sentence denotes However, eight subjects in the Azithromycin (AZM) group showed an increase in HIV-1 RNA levels in the 16th week, indicating the rapid emergence of viral resistance.
T95 4543-4748 Sentence denotes Contrarily, in the HCQ group, increased antiviral activity was revealed after 16 weeks rather than after 8 weeks, and no subject showed an increase in HIV-1 RNA levels at either 8 or 16 weeks of treatment.
T96 4749-4871 Sentence denotes This evidence suggests that no resistance developed under HCQ therapy or that it might develop more slowly than under ZDV.
T97 4872-5044 Sentence denotes A reduction in serum p24 antigen levels in both ZDV and HCQ groups was also described, while only in the HCQ group could a decrease in IL-6 and IgG levels be observed [18].
T98 5045-5244 Sentence denotes This reduction of IgG levels displayed after HCQ treatment in both studies may be significant since autoantibodies contribute to CD4+ cell depletion and autoimmune diseases observed in HIV infection.
T99 5245-5530 Sentence denotes Further, as lymphoid tissue is considered the primary site of HIV reservoirs and a critical site affected by CD4+ T cells depletion, the HCQ concentration was assessed in the plasma and adenoid tissue (At) of 8 HIV-infected patients administrating 400 or 800 mg of HCQ for eight weeks.
T100 5531-5662 Sentence denotes After taking these dosages, it was demonstrated that the mean HCQ concentration was significantly higher in At than in plasma [21].
T101 5663-5821 Sentence denotes This different drug distribution was also confirmed by an in vivo study using rabbits as an experimental model, receiving 15 mg/kg of HCQ subcutaneously [22].
T102 5822-5972 Sentence denotes Thus, the anti-HIV activity of HCQ could be linked to its accumulation in lymphoid tissue, a relevant site for HIV immunopathogenesis and replication.
T103 5973-6108 Sentence denotes Since monotherapy is not recommended in treating HIV, HCQ has also been tested in synergy with other drugs commonly used to manage HIV.
T104 6109-6358 Sentence denotes In this regard, 400 mg/day of HCQ in a combination regimen with 1000 mg/day hydroxyurea and 250–400 mg/day didanosine (dosed per body weight) was administered for 48 weeks to 22 asymptomatic HIV-1 infected patients naïve to antiretroviral treatment.
T105 6359-6401 Sentence denotes Only 16 out of 22 patients were evaluable.
T106 6402-6525 Sentence denotes These 16 subjects, at the 12th week, showed a significant reduction in viral load which was maintained until the 48th week.
T107 6526-6653 Sentence denotes Furthermore, at week 12, an increase in CD4+ percentage was also shown, and this improvement was kept until the 48th week [19].
T108 6654-6819 Sentence denotes To evaluate the long-term efficacy and safety of HCQ, hydroxyurea, and didanosine combination, they were also tested on 17 HIV-infected naïve patients for 144 weeks.
T109 6820-6912 Sentence denotes All subjects received 200 mg HCQ, 500 mg hydroxyurea, and 125–200 mg didanosine twice daily.
T110 6913-6999 Sentence denotes Of the 17 patients who started treatment, 14 remained until the end of the 144th week.
T111 7000-7257 Sentence denotes After 114 weeks, viral load was reduced by 1.6 Log10 copies/mL under baseline (p < 0.001), eight patients (47%) had an unnoticeable viral load (< 400 copies/mL), and two patients (12%) had a measurable viral load, but resistance mutations were not detected.
T112 7258-7498 Sentence denotes Four patients (24%) had both detectable viral load and resistance mutation: one with both 62V and 65R and three with both 74V and 184V mutations; the latter three were assessed as didanosine resistant, while no resistance was found for HCQ.
T113 7499-7583 Sentence denotes However, in all cases, the viral load remained below the baseline at the 144th week.
T114 7584-7705 Sentence denotes The CD4+ cell count had increased significantly, while the percentage of CD8 cells was reduced up to the 144th week [20].
T115 7706-7938 Sentence denotes This HCQ noticeable impact on immune activation, thereby increasing CD4+ T cells, was also demonstrated in a prospective study conducted on 20 HIV-infected immunologic no responders treated with standard antiretroviral therapy [23].
T116 7939-8103 Sentence denotes These results suggested that the combination of HCQ, hydroxyurea, and didanosine could be a valid alternative to the highly active commercial HAART in HIV-patients.
T117 8104-8242 Sentence denotes Nonetheless, these latter studies have some limitations, such as the small number of subjects included and the absence of a control group.
T118 8243-8392 Sentence denotes Therefore, it is not possible to determine the contribution made by HCQ to the overall decrease in viral load obtained from the combination of drugs.
T119 8393-8625 Sentence denotes Anyway, the potential anti-HIV efficacy of HCQ, when added to existing treatment with an antiretroviral regimen, was also confirmed by a case report about a patient with HLA-B27-associated spondyloarthropathy and HIV infection [43].
T120 8626-8846 Sentence denotes In contrast to the results mentioned above has been published a randomized, double-blind, placebo-controlled trial performed on 83 patients to which 400 mg HCQ (n = 42) or placebo (n = 41) were administered for 48 weeks.
T121 8847-9048 Sentence denotes All patients were naïve to HAART or had stopped this therapy 22 months before the trial began; 17 subjects in the HCQ group and 8 in the placebo group interrupted study medication before the 48th week.
T122 9049-9243 Sentence denotes At the end of treatment, in the HCQ group, compared to placebo, patients showed a reduction in total CD4 cell count and a significant viral load increased from the 12th week above baseline [24].
T123 9244-9470 Sentence denotes Hence, based on these results, HCQ did not decrease immune activation in patients with chronic HIV infection who were naïve to HAART, as there was an increase in HIV viral replication and a negative effect on CD4+ cell counts.
T124 9471-9720 Sentence denotes In light of these results, there was the need to consider that the first two described clinical trials, which reported the antiviral effect of HCQ, were on short-term treatments (8 or 16 weeks) and that they used an HCQ dosage of 800 mg/day [17,18].
T125 9721-9836 Sentence denotes In contrast, the latter used only 400 mg/day [24], corresponding to the maximum recommended dose for long-time use.
T126 9837-10116 Sentence denotes Besides, the latter study also enrolled more patients than the other studies, and unlike the trial of Piconi et al. [23], which described significative effects in reducing immune activation after HCQ administration, was conducted in the absence of antiretroviral treatments [24].
T127 10117-10308 Sentence denotes Therefore, further clinical trials involving a larger number of subjects would be necessary to assess the real antiviral activity of HCQ in monotherapy and synergy with antiretrovirals drugs.
T128 10309-10522 Sentence denotes Finally, assuming that women resistant to HIV infection show a low activation of the immune system at the level of the female genital tract (FGT), HCQ has been investigated as a drug able to prevent HIV infection.
T129 10523-10649 Sentence denotes It has been shown that the “immune quiescent” state of HIV-resistant women keeps the immune response against pathogens intact.
T130 10650-10847 Sentence denotes For this reason, it was thought to induce pharmacologically, in a rabbit model, this immunological quiescence state through an intravaginal implant capable of providing a controlled release of HCQ.
T131 10848-11118 Sentence denotes Considering that a concentration above 6.48 μg/mL of HCQ was able to interfere with the gp120 glycosylation process, the vaginal implant was projected to release HCQ with the longest possible duration at a concentration greater than 4.34 μg/mL but lower than 21.7 μg/mL.
T132 11119-11367 Sentence denotes After six days, this implant improved mucosal epithelial integrity, reduced submucosal immune cell recruitment, decreased gene expression and protein of T cell activation markers, and minimized the activation of key pro-inflammatory mediators [25].
T133 11368-11526 Sentence denotes Hence, HCQ can be considered a promising drug able to maintain a low baseline level of immune activation and may also play a role in preventing HIV infection.
T134 11528-11534 Sentence denotes 2.2.2.
T135 11535-11552 Sentence denotes Chikungunya Virus
T136 11553-11700 Sentence denotes The single-stranded RNA virus, Chikungunya virus (CHIKV), is an alphavirus belonging to the Togaviridae family, spread mainly in America’s regions.
T137 11701-11821 Sentence denotes The usual CHIKV vectors are rodents, while humans are infected by Aedes albopictus and Aedes aegypti and mosquito bites.
T138 11822-12376 Sentence denotes The first incubation stage can vary between 2 and 12 days, and three phases follow it: (1) the acute viraemic phase, characterized by severe polyarthritis, fever, and a rash, generally resolving in three weeks; (2) the post-acute stage, identified by arthritis with the addition of synovial and periarticular inflammation, neuropathy, neuropsychiatric disorders, and peripheral vascular disorders, usually takes its time at the end of three months; (3) the chronic phase that appears when the symptoms of the previous phase do not end after three months.
T139 12377-12646 Sentence denotes Generally, the acute phase of CHIKV infections is treated with non-steroidal anti-inflammatory drugs (NSAIDs), while for the chronic persistent phase, treatments involving HCQ as monotherapy or combined with methotrexate (MTX) and/or sulfasalazine seem to be effective.
T140 12647-12782 Sentence denotes HCQ does not appear to affect the initial stage of infection, as demonstrated in a prospective randomized parallel-group study of 2009.
T141 12783-12904 Sentence denotes In this trial, combinations of NSAIDs, HCQ, and/or corticosteroids were assessed in patients with classic CHIKV features.
T142 12905-13072 Sentence denotes A total of 120 subjects were divided into groups treated with 200 mg/day aceclofenac (ACF), 400 mg/day HCQ, and 10 mg/day prednisolone (PRD) in different combinations.
T143 13073-13139 Sentence denotes Only 114 subjects remained until the end of the trial (six weeks).
T144 13140-13405 Sentence denotes It was seen that HCQ had no benefit in the early stages of CHIKV infection and also in the reduction of the VAS (used for pain assessment) and in the improvement of Barthel’s indexes (used for instrumental activities of daily living and activities of daily living).
T145 13406-13491 Sentence denotes In fact, there was no difference between groups treated with ACF + HCQ and ACF alone.
T146 13492-13593 Sentence denotes Similarly, the combination of ACF + HCQ + PRD did not add any additional benefit over ACF + PRD [26].
T147 13594-13675 Sentence denotes In contrast, HCQ seems to affect the improvement of CHIKV chronic phase diseases.
T148 13676-13816 Sentence denotes In a recent multicenter study, the efficacy of HCQ was evaluated in 39 patients with rheumatic manifestation related to CHIKV chronic phase.
T149 13817-14013 Sentence denotes In four subjects, the treatment was interrupted due to the onset of side effects such as nausea, stomatitis, rash, headache, while the evolution of CHIKV disease was evaluated in only 22 patients.
T150 14014-14199 Sentence denotes After three months of treatment, evidence of synovitis was disappeared in 10 of 20 subjects (50%) with swollen joins while complete remission was verified in five patients (19.2%) [27].
T151 14200-14346 Sentence denotes However, another study demonstrated that the effects of HCQ in combination with MXT and sulfasalazine were superior to those shown in monotherapy.
T152 14347-14556 Sentence denotes In particular, in a randomized controlled open-label study, the impact of HCQ in monotherapy or association with MTX and sulfasalazine was assessed in 72 patients with chronic persistent chikungunya arthritis.
T153 14557-14735 Sentence denotes In this trial, 400 mg/day HCQ were administrated to 35 subjects, while a combination of 15 mg/day MTX, 1 g/day sulfasalazine, and 400 mg/day HCQ was administrated to 37 patients.
T154 14736-14862 Sentence denotes Either treatment lasted 24 weeks and for the first 6 weeks, both groups received an escalated dose of prednisone (7.5 mg/day).
T155 14863-14985 Sentence denotes At the end of the 24th week, only the combination of drugs improved disease activity and reduced disability and pain [28].
T156 14986-15248 Sentence denotes These results, following those obtained in a previous uncontrolled 16-week study, since a reduction in ACR score was shown after MTX (15–20 mg/weekly) and HCQ (400 mg/day) administration to CHIKV infected patients with persistent inflammatory polyarthritis [29].
T157 15249-15351 Sentence denotes The results obtained could be explained with the different characterization of virus infection phases.
T158 15352-15636 Sentence denotes It is known that while the acute phase of CHIKV infections is due to the development of viremia, the chronic phase is closely related to an immune-mediated phenomenon, as pro-inflammatory cytokines and chemokines play important roles in the pathogenesis of chikungunya arthritis [44].
T159 15637-15925 Sentence denotes Therefore, considering the results obtained from these clinical studies, it is possible to say that although HCQ does not affect viremia reduction, as demonstrated by the lack of activity in the first phase of infection, it can improve the chronic phase diseases by reducing inflammation.
T160 15927-15933 Sentence denotes 2.2.3.
T161 15934-15946 Sentence denotes Flaviviruses
T162 15947-16184 Sentence denotes Hepatitis virus, an RNA virus belonging to the Flaviviridae family, is closely related to liver disease, which in 70–80% of patients becomes chronic, resulting in major complications such as cirrhosis and, in the year, also liver cancer.
T163 16185-16281 Sentence denotes The antiviral activity of HCQ on the hepatitis C virus (HCV) in monotherapy has not been tested.
T164 16282-16364 Sentence denotes However, it seems that this drug increases the antiviral effect of standard drugs.
T165 16365-16607 Sentence denotes In a study including 120 Egyptian patients infected by the hepatitis C virus, it was seen that the combination of HCQ with pegylated interferon and ribavirin could improve biochemical and virological responses in chronic hepatitis C subjects.
T166 16608-16865 Sentence denotes All patients were randomized and divided into two groups; the control group treated with standard-of-care (SOC) consisted of 160 µg of subcutaneous pegylated interferon and 1000–12000 mg/day of oral ribavirin, and the group treated with 200 mg HCQ plus SOC.
T167 16866-17042 Sentence denotes At the end of the treatment (12 weeks), patients of HCQ + SOC group showed a high virological response compared to the control group (54/60 (90%) vs. 43/60 (71.7%); p = 0.011).
T168 17043-17261 Sentence denotes Moreover, in the HCQ + SOC group, there was a normalization of ALT levels, as is also demonstrated by the earlier biochemical response (EBR) highlighted in HCQ + SOC group 58/60 (96.7%) than SOC group 42/60 (70%) [30].
T169 17262-17388 Sentence denotes These results were confirmed by several case reports regarding patient treatment with Porphyria Cutanea Tarda and Hepatitis C.
T170 17389-17581 Sentence denotes It was seen that a low dose of HCQ (100 mg twice weekly) prevented the recurrence of Porphyria Tarda and reduced the viral response during HCV therapy, including ribavirin and interferon [45].
T171 17582-17839 Sentence denotes Furthermore, in a patient with chronic hepatitis and rheumatoid arthritis, a low risk for hepatitis virus reactivation was observed after treatment with steroids (< 7.5 mg/day), HCQ or sulfadiazine [46] in combination with antivirals as prophylaxis [47,48].
T172 17840-18008 Sentence denotes Another possible antiviral effect of HCQ is exerted on Zika virus (ZIKV), an RNA virus of the Flaviviridae family transmitted by numerous mosquitoes of the genus Aedes.
T173 18009-18196 Sentence denotes No clinical studies have been conducted yet, but an in vivo study has demonstrated the ability of HCQ to attenuate vertical transmission of ZIKV by reducing placental and fetal infection.
T174 18197-18330 Sentence denotes In this study, pregnant mice were treated with 40 mg/kg/day HCQ via intraperitoneal injection beginning one day after ZIKV infection.
T175 18331-18497 Sentence denotes It was seen that HCQ acted as an autophagy inhibitor by increasing p62 levels in trophoblast and thus reducing placental ZIKV infection and fetal growth defects [31].
T176 18498-18609 Sentence denotes To date, no clinical trials have been conducted to evaluate HCQ antiviral effects in patients infected by ZIKV.
T177 18611-18617 Sentence denotes 2.2.4.
T178 18618-18645 Sentence denotes Coronavirus Disease of 2019
T179 18646-18856 Sentence denotes Coronaviruses, belonging to the Coronaviridae family, are enveloped positive-sense single-stranded RNA viruses highly distributed in humans and vertebrates like bats, which are proposed as their main reservoir.
T180 18857-19039 Sentence denotes Specifically, Coronavirus Disease of 2019 (COVID-19) was first identified in December 2019 in Wuhan, the capital city of Hubei (China), and it is caused by the SARS-CoV-2 virus [49].
T181 19040-19214 Sentence denotes Since COVID-19 has spread rapidly in many countries, it has quickly become a global pandemic, so it is necessary to develop drugs able to exert antiviral activity against it.
T182 19215-19310 Sentence denotes A recent study showed HCQ in vitro antiviral activity against SARS-CoV-2 (EC50 = 0.72 μM) [50].
T183 19311-19512 Sentence denotes HCQ seemed to be able to inhibit the first step of the viral replication cycle by interfering with the link between spike (S) viral protein and the angiotensin-converting enzyme 2 (ACE-2) receptor [8].
T184 19513-19672 Sentence denotes It would also appear that HCQ was able to induce changes in cell membrane pH resulting in reduced viral entry and inhibition of the last stages of replication.
T185 19673-19795 Sentence denotes Moreover, HCQ may abolish the cytokine storm related to the advanced stages of COVID-19 through immunomodulatory activity.
T186 19796-19905 Sentence denotes To date, several clinical studies are underway to evaluate the efficacy of HCQ for the treatment of COVID-19.
T187 19906-20052 Sentence denotes In a randomized clinical trial conducted in China, 62 patients with COVID-19 were randomly assigned to two groups: the control and the HCQ groups.
T188 20053-20291 Sentence denotes Either group received standard treatment including antiviral agents, oxygen therapy, immunoglobulin, and antibacterial agents, with or without corticosteroids, but patients in the HCQ group also received oral HCQ 400 mg/day for five days.
T189 20292-20437 Sentence denotes During treatment, clinical characteristics, clinical recovery time (TTCR), and radiological results were assessed to determine the effect of HCQ.
T190 20438-20687 Sentence denotes It was seen that in the HCQ group, the recovery time of body temperature was shorter than in the control group and that the cough remission time was also significantly decreased, while only patients in the control group progressed to severe illness.
T191 20688-20784 Sentence denotes Furthermore, in the HCQ group, 61.3% of patients showed significant absorption of pneumonia [6].
T192 20785-20917 Sentence denotes In another open-label non-randomized French clinical trial, the efficiency of HCQ in reducing the viral count was also demonstrated.
T193 20918-20974 Sentence denotes In this study, 36 subjects were divided into two groups:
T194 20975-21070 Sentence denotes 16 patients for the control group and 20 subjects for HCQ who were administered 600 mg/day HCQ.
T195 21071-21236 Sentence denotes Among the HCQ group, six patients also received 500 mg of AZM for the first day, followed by 250 mg/day for the next four days to prevent super bacterial infections.
T196 21237-21382 Sentence denotes PCR results from nasopharyngeal samples were negative for 70% of patients treated with HCQ and 12.5% in the control group (p = 0.001) on day six.
T197 21383-21631 Sentence denotes Furthermore, when the effect of HCQ as monotherapy was compared to that of HCQ + AZM, it was found that at day six, 100% of HCQ + AZM treated subjects were virologically negative compared with 57.1% of patients treated with HCQ as monotherapy [32].
T198 21632-21849 Sentence denotes These results suggest a synergistic effect between HCQ and AZM and are supported by an uncontrolled non-comparative observational study conducted by the same France group, in a cohort of 80 slightly infected patients.
T199 21850-22017 Sentence denotes In this study, HCQ + AZM treated people were 83% virologically negative on day 7 and 93% on day 8; after 10 days of treatment, only 2 subjects still remain contagious.
T200 22018-22142 Sentence denotes Furthermore, the average duration of hospitalization was found to be 4.6 days after the administration of HCQ plus AZM [33].
T201 22143-22224 Sentence denotes However, these last two studies have a limit, as Gautret et al. carried both out.
T202 22225-22400 Sentence denotes In particular, in the first study, data are available up to 6 days despite the planned 10 days, and in the second study, 6 patients from the previous study were also included.
T203 22401-22599 Sentence denotes Gautret also conducted a retrospective analysis of 1061 cases in which, after treatment with HCQ + AZM, good virological care and clinical outcomes were found in 973 patients (91.7%) within 10 days.
T204 22600-22769 Sentence denotes A prolonged viral carriage was observed in only 47 (4.4%) subjects with a high viral load at the moment of hospitalization, but on day 10 the viral culture was negative.
T205 22770-22823 Sentence denotes Finally, all but one on day 15 were PCR cleared [51].
T206 22824-22959 Sentence denotes By contrast, there are results obtained by several clinical studies that dismiss the possible use of HCQ for the treatment of COVID-19.
T207 22960-23305 Sentence denotes In particular, a prospective study on 11 severe COVID-19 infected patients treated with the same dosage used by Gautret et al. (600 mg/day HCQ and 500 mg AZM for the first day followed by 250 mg/day from day 2 to 5) was shown to provide no evidence of clinical benefits or a strong antiviral activity through the combination of HCQ and AZM [34].
T208 23306-23521 Sentence denotes The ineffectiveness of HCQ has also been declared in a multicenter, open-label, randomized controlled trial involving 150 hospitalized infected patients (148 with mild or moderate disease and 2 with severe disease).
T209 23522-23720 Sentence denotes All subjects were divided into two groups (in a 1:1 ratio): the control group that received only SOC, consisting of antiviral, glucocorticoid, and antiviral, and the group treated with HCQ plus SOC.
T210 23721-23876 Sentence denotes The administrated dose of HCQ consisted of 200 mg/day for the first three days, followed by 800 mg/day as maintained dosage until the end of the treatment.
T211 23877-24016 Sentence denotes After 28 days of treatment, there was no significant difference in SARS-CoV-2 negative conversion in either the HCQ + SOC or the SOC group.
T212 24017-24207 Sentence denotes Similarly, there were no significant differences in the median time to negative conversion and the probability of symptom alleviation within 28 days between HCQ + SOC and the SOC group [35].
T213 24208-24355 Sentence denotes Another multicenter, randomized controlled Egyptian trial evaluated, in 194 subjects with COVID-19, the safety and efficacy of HCQ compared to SOC.
T214 24356-24582 Sentence denotes In terms of mechanical ventilation need and mortality, the addition of HCQ (400 mg twice daily (in day 1) followed by 200 mg tablets twice daily) to SOC was not associated with an improvement of COVID-19 patients’ health [36].
T215 24583-24707 Sentence denotes These results were confirmed by a recent randomized, double-blind, placebo-controlled trial conducted in the USA and Canada.
T216 24708-24942 Sentence denotes In this study, 419 early and mild COVID-19 subjects were randomly assigned to two groups, the HCQ group treated with 800 mg HCQ once, followed by 600 mg in 6 to 8 h, then 600 mg daily for 4 more days, and the placebo or control group.
T217 24943-25212 Sentence denotes Within 14 days of treatment, there was no change in the severity of symptoms in non-hospitalized patients between the HCQ group and the placebo group (difference in symptom severity: relative, 12%; absolute, −0.27 points (95% CI, −0.61 to 0.07 points); p = 0.117) [37].
T218 25213-25408 Sentence denotes Likewise, 2 studies carried out by Mahévas et al. supported the ineffectiveness of HCQ and highlighted that HCQ administration to COVID-10 patients was highly related to ECG modification [38,39].
T219 25409-25611 Sentence denotes ECG modification, resulting in QT-interval prolongation, is a characteristic side effect associated with HCQ treatment that has been shown in several clinical studies on patients infected with COVID-19.
T220 25612-25811 Sentence denotes In particular, the risk of QT-interval prolongation was increased when HCQ was associated with AZM, as demonstrated in a cohort of 84 patients who received 400 mg twice-daily HCQ plus 500 mg/day AZM.
T221 25812-25987 Sentence denotes In these patients, on day 3.6 ± 1.6 of therapy, the EGC showed a QTc prolongation from a baseline average of 435 ± 24 ms (mean ± SD) to a maximal average value of 463 ± 32 ms.
T222 25988-26156 Sentence denotes Moreover, in nine subjects (11%) there was a severe prolongation of QTc to > 500 ms (baseline average of 447 ± 30 ms to 527 ± 17 ms (p < 0.01 (one-sample t-test)) [52].
T223 26157-26270 Sentence denotes This complication was also confirmed in a retrospective study of 251 COVID-19 patients treated with HCQ/AZM [53].
T224 26271-26398 Sentence denotes It seems that a predictor of extreme QTc prolongation was renal failure and that its incidence increased with longer treatment.
T225 26399-26676 Sentence denotes The probability of QTc prolongation may also increase in the presence of other factors such as previous cardiovascular diseases, metabolic degeneration (hypoxia, pH, multiorgan system failure, and electrolyte abnormalities), age, and sex (females seem to be more at risk) [54].
T226 26677-26962 Sentence denotes Therefore, since QTc prolongation to more than 500 ms is known to be associated with a high risk for malignant arrhythmia and fatal stroke, recent guidance suggests the ECG screening with QTc evaluation in COVID-19-infected patients treated with novel therapies including HCQ/AZM [55].
T227 26963-27265 Sentence denotes It has also been suggested that the use of drugs that block late sodium channels (mexiletine or lidocaine) and close attention to serum electrolytes, in addition to the evaluation of heart rate and QT intervals, may allow the administration of HCQ/AZM even in subjects with prolonged QT intervals [54].
T228 27266-27411 Sentence denotes Despite the lack of real antiviral evidence related to HCQ administration, this drug has also been investigated as a possible prophylactic agent.
T229 27412-27615 Sentence denotes In fact, the pharmacokinetics of HCQ, like its long half-life and the high concentration in the lung (500-times higher than blood concentration), has made it an ideal candidate for prophylactic use [56].
T230 27616-27761 Sentence denotes The first study conducted on this line was performed in South Korea on 211 virus-exposed individuals, including 189 patients and 22 care-workers.
T231 27762-27994 Sentence denotes The HCQ administration (400 mg day) as post-exposure prophylaxis resulted in the negative follow-up PCR tests after the end of 14 days of quarantine period (only 97.4% of patients and 95.5% of care-workers completed the study) [40].
T232 27995-28163 Sentence denotes However, it is necessary to consider that this is a single-center clinical study with a high risk of bias and that a subsequent randomized clinical study has denied it.
T233 28164-28328 Sentence denotes In particular, Boulware D.R. et al., in a randomized, double-blind, placebo-controlled trial, tested HCQ as a prophylactic agent within 4 days after virus exposure.
T234 28329-28510 Sentence denotes There were 821 asymptomatic participants randomly assigned to receive either placebo or HCQ (800 mg once, followed by 600 mg in 6 to 8 h, then 600 mg per day for 4 additional days).
T235 28511-28806 Sentence denotes After 14 days of treatment, it was demonstrated that HCQ did not prevent COVID-19 infection when compared to placebo, since the incidence of illnesses compatible with Covid-19 disease did not differ significantly between subjects receiving HCQ (49 of 414 (11.8%)) or placebo (58 of 407 (14.3%)).
T236 28807-28929 Sentence denotes Furthermore, the onset of side effects was more frequent in patients treated with HCQ than placebo (40.1% vs. 16.8%) [41].
T237 28930-29092 Sentence denotes To better assess the incidence of side effects linked to HCQ administration as post-exposure prophylaxis, a cross-sectional study was conducted among 140 doctors.
T238 29093-29341 Sentence denotes Sixty nine adverse events were documented in 44 subjects (31%); the most common reported symptoms were headache followed by nausea, dizziness, abdominal cramps, and loose stools, while hypoglycemia was seen in only three diabetic participants [57].
T239 29342-29493 Sentence denotes Hence, even if the side effects highlighted were not serious, it is recommended to take the utmost care before using HCQ for COVID-19 chemoprophylaxis.
T240 29494-29624 Sentence denotes The ineffectiveness of HCQ administration as post-exposure prophylaxis has also been demonstrated by an in vivo study on macaques.
T241 29625-29759 Sentence denotes Maisonnasse P. et al. tested different treatment strategies, including HCQ alone or in combination with AZM, in comparison to placebo.
T242 29760-29825 Sentence denotes All the treatments were administrated before or after viral load.
T243 29826-29959 Sentence denotes It was seen that when HCQ was administrated as pre-exposure prophylaxis, it did not protect against the acquisition of the infection.
T244 29960-30132 Sentence denotes Similarly, neither HCQ nor HCQ + AZM had beneficial effects in improving viral infection’s symptoms [58], confirming previously analyzed clinical studies’ negative results.
T245 30133-30320 Sentence denotes Several case reports have supported all these results since people already using HCQ for a long time to treat inflammatory diseases also showed severe illness related to COVID-19 [59,60].
T246 30321-30515 Sentence denotes In the light of collected data, despite the success of the first clinical trials, the latest studies have shown the ineffectiveness of HCQ for the treatment and prevention of COVID-19 infection.
T247 30516-30536 Sentence denotes So that, if the U.S.
T248 30537-30830 Sentence denotes Food and Drug Administration (FDA) had initially authorized the use of HCQ in case of emergency [61], in June 2020, the FDA revoked this authorization [62] since the potential HCQ effectiveness in treating COVID-19 was overtaken by severe cardiac adverse events and other serious side effects.
T249 30831-31074 Sentence denotes In fact, there is the need to consider that in subjects with severe COVID-19, the abundance of inflammatory molecules like interleukins and tumor necrosis factors generate a cytokine storm, leading to a septic shock and multiple organ failure.
T250 31075-31181 Sentence denotes In hepatic and renal dysfunction, HCQ metabolism and clearance were compromised and its safety is altered.
T251 31182-31417 Sentence denotes Moreover, recently the Surviving Sepsis Campaign guidelines on the management of critically ill patients with COVID-19 concluded that there was insufficient evidence to recommend the routine use of HCQ in patients admitted in ICU [63].
T252 31418-31545 Sentence denotes In the same way, the American College of Physicians practice guidelines do not recommend HCQ for prophylaxis or treatment [64].
T253 31546-31806 Sentence denotes International trials like SOLIDARITY (International trial by World Health Organisation) [65], RECOVERY (Randomised Evaluation of Covid-19 Therapy) [66], and DISCOVERY (Trial of Treatments for COVID-19 in Hospitalized Adults) [67] have also stopped the HCQ arm.
T254 31807-32037 Sentence denotes In particular, the World Health Organisation (WHO), in the SOLIDARITY trial project, has arrested all arms involving HCQ, as evidence showed that it did not reduce the mortality of hospitalized COVID-19 patients compared with SOC.
T255 32038-32177 Sentence denotes However, this decision was not applied to HCQ use or evaluation in pre- or post-exposure prophylaxis for subjects exposed to COVID-19 [68].
T256 32178-32268 Sentence denotes To conclude, the HCQ treatment of SARS-CoV-2 infection was not met with its hoped success.
T257 32269-32426 Sentence denotes This is probably related to the inability of the dosing regimens currently in use to achieve the blood concentration required for the HCQ antiviral activity.
T258 32427-32665 Sentence denotes Initially, based on physiological pharmacokinetic models, Yao et al. recommended for SARS-CoV-2 infection a loading oral HCQ dose of 400 mg twice daily, followed by a maintenance dose of 200 mg administered twice daily for four days [50].
T259 32666-33003 Sentence denotes However, this recommended HCQ dosage regimen was based only on the ratio of free lung trough concentration to in vitro EC50 values (the EC50 of HCQ for SARS-CoV-2 ranged between 0.72 and 17.31µM) and did not consider the tendency of HCQ to accumulate within acidic cellular organelles like endosomes, lysosomes, and Golgi apparatus [69].
T260 33004-33159 Sentence denotes In fact, it has been demonstrated that HCQ concentration in lysosomes is higher than the extracellular concentration (80 µM vs. 0.5 µM, respectively) [70].
T261 33160-33323 Sentence denotes Based on these results, it was considered necessary to compare the EC50 values obtained in vitro with the plasma concentration and not with the lung concentration.
T262 33324-33612 Sentence denotes In a study investigating HCQ pharmacokinetics in COVID-19 patients treated with 600 mg/day of HCQ, it was found that the mean blood concentration of HCQ was 0.46 mg/day [32], which was below the lowest estimated levels of 0.48 mg/mL corresponding to the in vitro concentration of 0.72 µM.
T263 33613-33820 Sentence denotes Further, a plasma concentration predicted for HCQ antiviral EC50 made by Garcia-Cremades et al. found that it should be 4,7 µM corresponding to 1.58 mg/mL, which is much higher than in vivo plasmatic values.
T264 33821-34011 Sentence denotes To reach this plasma concentration, it should be necessary to take an amount of HCQ higher than 400 mg twice a day for five days or more [71], which would increase the onset of side effects.
T265 34012-34265 Sentence denotes Thus, the ineffectiveness of HCQ antiviral activity again SARS-CoV-2 can be related to the low current dosing regimens and the impossibility to increase the administered doses due to the increased risk of severe side effects, especially QT prolongation.