| 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. |
