Klorokin ili hidroksiklorokin za prevenciju i liječenje COVID-19.
The Cochrane database of systematic reviews
Sažetak istraživanja
Pozadina Pandemija bolesti korona virusa 2019. (COVID-19) rezultirala je značajnom smrtnošću. Neki stručnjaci su predložili hlorokin (CQ) i hidroksihlorokin (HCQ) za lečenje ili prevenciju bolesti. Efikasnost i sigurnost ovih lijekova procijenjene su u randomiziranim kontroliranim studijama.
Ciljevi Procijeniti efekte hlorokina (CQ) ili hidroksihlorokina (HCQ) za 1) liječenje ljudi sa COVID-19 na smrt i vrijeme do uklanjanja virusa; 2) prevenciju infekcije kod osoba koje su u riziku od izloženosti SARS-CoV-2; 3) sprečavanje infekcije kod osoba izloženih SARS-CoV-2.
Metode pretraživanja Pretražili smo Cochrane Centralni registar kontrolisanih ispitivanja (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www. controlled-trials. com) i resurse specifične za COVID-19 www. covid-nma. com i covid-19. cochrane. org, za studije bilo kojeg statusa publikacije i na bilo kom jeziku. Izvršili smo sve pretrage do 15. septembra 2020. Kontaktirali smo istraživače kako bismo identificirali neobjavljene studije koje su u toku. Kriterijumi odabira Uključili smo randomizirana kontrolirana ispitivanja (RCT) koja testiraju hlorokin ili hidroksihlorokin kod osoba sa COVID-19, osoba u riziku od izloženosti COVID-19 i osoba izloženih COVID-19. Neželjeni događaji (bilo koji, ozbiljni i produženje QT intervala na elektrokardiogramu) su takođe izdvojeni. Prikupljanje i analiza podataka Dva autora pregleda su nezavisno procijenila podobnost rezultata pretraživanja, izvukla podatke iz uključenih studija i procijenila rizik od pristrasnosti koristeći Cochrane alatku „Rizik od pristrasnosti“. Kontaktirali smo autore studije radi pojašnjenja i dodatnih podataka za neke studije. Koristili smo omjere rizika (RR) za dihotomne ishode i srednje razlike (MD) za kontinuirane ishode, sa 95% intervalima povjerenja (CI). Izvršili smo meta-analizu koristeći model slučajnih efekata za ishode gdje je objedinjavanje procjena efekta bilo prikladno. Glavni rezultati 1. Liječenje bolesti COVID-19 Uključili smo 12 ispitivanja koja su uključivala 8569 učesnika, od kojih su svi bili odrasli. Studije su bile iz Kine (4); Brazil, Egipat, Iran, Španija, Tajvan, Velika Britanija i Sjeverna Amerika (svaka 1 studija); i globalna studija u 30 zemalja (1 studija). Devet je bilo na hospitalizovanim pacijentima, a troje na ambulantnoj nezi. Ozbiljnost bolesti, prevalencija komorbiditeta i upotreba zajedničkih intervencija značajno su varirali između studija. Pronašli smo potencijalne rizike od pristrasnosti u svim domenima u nekoliko ispitivanja. Devet studija je upoređivalo HCQ sa standardnom negom (7779 učesnika), a jedno je upoređivalo HCQ sa placebom (491 učesnik); rasporedi doziranja su varirali. HCQ ima malu ili nikakvu razliku u smrti zbog bilo kojeg uzroka (RR 1.09, 95% CI 0.99 do 1.19; 8208 učesnika; 9 ispitivanja; dokazi visoke sigurnosti). Analiza osjetljivosti koristeći modificirane rezultate s namjerom liječenja iz tri ispitivanja nije utjecala na zbirnu procjenu efekta. HCQ može imati malu ili nikakvu razliku u odnosu na udio ljudi koji imaju negativan PCR na SARS-CoV-2 na respiratornim uzorcima 14. dana od upisa (RR 1.00, 95% CI 0.91 do 1.10; 213 učesnika; 3 ispitivanja; dokazi niske sigurnosti). HCQ vjerovatno rezultira malo ili nimalo razlike u napredovanju do mehaničke ventilacije (RR 1.11, 95% CI 0.91 do 1.37; 4521 učesnika; 3 ispitivanja; dokazi umjerene sigurnosti). HCQ vjerovatno rezultira skoro trostruko povećanim rizikom od neželjenih događaja (RR 2.90, 95% CI 1.49 do 5. 64; 1394 učesnika; 6 pokušaja; dokazi umjerene sigurnosti), ali mogu imati malu ili nikakvu razliku u riziku od ozbiljnih neželjenih događaja (RR 0,82, 95% CI 0,37 do 1,79; 1004 učesnika; 6 ispitivanja; dokazi niske sigurnosti). Veoma smo nesigurni u pogledu efekta HCQ na vrijeme do kliničkog poboljšanja ili rizika od produženja QT intervala na elektrokardiogramu (dokazi vrlo niske sigurnosti). Jedno ispitivanje (22 učesnika) randomiziralo je pacijente na CQ u odnosu na lopinavir/ritonavir, lijek nepoznate djelotvornosti protiv SARS-CoV-2, i nije prijavio nikakvu razliku u kliničkom oporavku ili nuspojavama. Jedno ispitivanje je upoređivalo HCQ u kombinaciji sa azitromicinom u odnosu na standardnu njegu (444 učesnika). Ovo ispitivanje nije otkrilo razliku u smrti, potrebi za mehaničkom ventilacijom, dužini prijema u bolnicu ili ozbiljnim štetnim događajima. Prijavljen je veći rizik od neželjenih događaja u grupi koja je primala HCQ i azitromicin; ovo uključuje produženje QT intervala, kada se meri. Jedno ispitivanje je upoređivalo HCQ sa febuksostatom, drugim lekom nepoznate efikasnosti protiv SARS-CoV-2 (60 učesnika). Nije otkrivena razlika u riziku od hospitalizacije ili promjene u izgledu pluća na kompjuterskoj tomografiji (CT); nije prijavljen nijedan smrtni slučaj. 2. Prevencija bolesti COVID-19 kod ljudi koji su u riziku od izloženosti SARS-CoV-2 Tekuća ispitivanja tek treba da objave rezultate za ovaj cilj. 3. Prevencija bolesti COVID-19 kod ljudi koji su bili izloženi SARS-CoV-2 Jedno ispitivanje (821 učesnik) uporedilo je HCQ sa placebom kao profilaktičkim agensom u SAD (oko 90% učesnika) i Kanadi. Angažovani su asimptomatski odrasli (66% zdravstvenih radnika; srednja starost 40 godina; 73% bez komorbiditeta) sa istorijom izloženosti osobama sa potvrđenim COVID-19. Veoma smo nesigurni u pogledu efekta HCQ na primarne ishode, za koje je prijavljeno nekoliko događaja: 20/821 (2,4%) razvilo je potvrđeni COVID-19 14 dana od upisa, a 2/821 (0,2%) je hospitalizirano zbog COVID-19 (dokazi vrlo niske sigurnosti). HCQ vjerovatno povećava rizik od neželjenih događaja u poređenju sa placebom (RR 2.39, 95% CI 1.83 do 3.11; 700 učesnika; 1 ispitivanje; dokaz umjerene sigurnosti). HCQ može dovesti do male ili nikakve razlike u ozbiljnim nuspojavama (nema RR: nijedan učesnik nije doživio ozbiljne nuspojave; dokazi niske sigurnosti). Jedno klaster randomizirano ispitivanje (2525 učesnika) uporedilo je HCQ sa standardnom njegom za prevenciju COVID-19 kod ljudi koji su bili izloženi SARS-CoV-2 u Španiji. Većina učesnika radila je ili boravila u staračkim domovima; prosječna starost je bila 49 godina. Nije bilo razlike u riziku od simptomatskog potvrđenog COVID-19 ili proizvodnje antitijela na SARS-CoV-2 između dvije grupe istraživanja.
Zaključci autora HCQ za osobe zaražene COVID-19 ima mali ili nikakav utjecaj na rizik od smrti i vjerovatno nema utjecaja na prelazak na mehaničku ventilaciju. Neželjeni događaji su utrostručeni u odnosu na placebo, ali je pronađeno vrlo malo ozbiljnih nuspojava. Ne treba provoditi daljnja ispitivanja hidroksihlorokina ili hlorokina za liječenje. Ovi rezultati smanjuju vjerovatnoću da je lijek efikasan u zaštiti ljudi od infekcije, iako to nije u potpunosti isključeno. Vjerovatno je razumno dovršiti ispitivanja koja ispituju prevenciju infekcije i osigurati da se oni provode po visokim standardima kako bi se dobili nedvosmisleni rezultati.
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Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.
Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial mortality. Some specialists proposed chloroquine (CQ) and hydroxychloroquine (HCQ) for treating or preventing the disease. The efficacy and safety of these drugs have been assessed in randomized controlled trials.
Objectives To evaluate the effects of chloroquine (CQ) or hydroxychloroquine (HCQ) for 1) treating people with COVID-19 on death and time to clearance of the virus; 2) preventing infection in people at risk of SARS-CoV-2 exposure; 3) preventing infection in people exposed to SARS-CoV-2. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Current Controlled Trials (www.controlled-trials.com), and the COVID-19-specific resources www.covid-nma.com and covid-19.cochrane.org, for studies of any publication status and in any language. We performed all searches up to 15 September 2020. We contacted researchers to identify unpublished and ongoing studies. Selection criteria We included randomized controlled trials (RCTs) testing chloroquine or hydroxychloroquine in people with COVID-19, people at risk of COVID-19 exposure, and people exposed to COVID-19. Adverse events (any, serious, and QT-interval prolongation on electrocardiogram) were also extracted. Data collection and analysis Two review authors independently assessed eligibility of search results, extracted data from the included studies, and assessed risk of bias using the Cochrane 'Risk of bias' tool. We contacted study authors for clarification and additional data for some studies. We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CIs). We performed meta-analysis using a random-effects model for outcomes where pooling of effect estimates was appropriate. Main results 1. Treatment of COVID-19 disease We included 12 trials involving 8569 participants, all of whom were adults. Studies were from China (4); Brazil, Egypt, Iran, Spain, Taiwan, the UK, and North America (each 1 study); and a global study in 30 countries (1 study). Nine were in hospitalized patients, and three from ambulatory care. Disease severity, prevalence of comorbidities, and use of co-interventions varied substantially between trials. We found potential risks of bias across all domains for several trials. Nine trials compared HCQ with standard care (7779 participants), and one compared HCQ with placebo (491 participants); dosing schedules varied. HCQ makes little or no difference to death due to any cause (RR 1.09, 95% CI 0.99 to 1.19; 8208 participants; 9 trials; high-certainty evidence). A sensitivity analysis using modified intention-to-treat results from three trials did not influence the pooled effect estimate. HCQ may make little or no difference to the proportion of people having negative PCR for SARS-CoV-2 on respiratory samples at day 14 from enrolment (RR 1.00, 95% CI 0.91 to 1.10; 213 participants; 3 trials; low-certainty evidence). HCQ probably results in little to no difference in progression to mechanical ventilation (RR 1.11, 95% CI 0.91 to 1.37; 4521 participants; 3 trials; moderate-certainty evidence). HCQ probably results in an almost three-fold increased risk of adverse events (RR 2.90, 95% CI 1.49 to 5.64; 1394 participants; 6 trials; moderate-certainty evidence), but may make little or no difference to the risk of serious adverse events (RR 0.82, 95% CI 0.37 to 1.79; 1004 participants; 6 trials; low-certainty evidence). We are very uncertain about the effect of HCQ on time to clinical improvement or risk of prolongation of QT-interval on electrocardiogram (very low-certainty evidence). One trial (22 participants) randomized patients to CQ versus lopinavir/ritonavir, a drug with unknown efficacy against SARS-CoV-2, and did not report any difference for clinical recovery or adverse events. One trial compared HCQ combined with azithromycin against standard care (444 participants). This trial did not detect a difference in death, requirement for mechanical ventilation, length of hospital admission, or serious adverse events. A higher risk of adverse events was reported in the HCQ-and-azithromycin arm; this included QT-interval prolongation, when measured. One trial compared HCQ with febuxostat, another drug with unknown efficacy against SARS-CoV-2 (60 participants). There was no difference detected in risk of hospitalization or change in computed tomography (CT) scan appearance of the lungs; no deaths were reported. 2. Preventing COVID-19 disease in people at risk of exposure to SARS-CoV-2 Ongoing trials are yet to report results for this objective. 3. Preventing COVID-19 disease in people who have been exposed to SARS-CoV-2 One trial (821 participants) compared HCQ with placebo as a prophylactic agent in the USA (around 90% of participants) and Canada. Asymptomatic adults (66% healthcare workers; mean age 40 years; 73% without comorbidity) with a history of exposure to people with confirmed COVID-19 were recruited. We are very uncertain about the effect of HCQ on the primary outcomes, for which few events were reported: 20/821 (2.4%) developed confirmed COVID-19 at 14 days from enrolment, and 2/821 (0.2%) were hospitalized due to COVID-19 (very low-certainty evidence). HCQ probably increases the risk of adverse events compared with placebo (RR 2.39, 95% CI 1.83 to 3.11; 700 participants; 1 trial; moderate-certainty evidence). HCQ may result in little or no difference in serious adverse events (no RR: no participants experienced serious adverse events; low-certainty evidence). One cluster-randomized trial (2525 participants) compared HCQ with standard care for the prevention of COVID-19 in people with a history of exposure to SARS-CoV-2 in Spain. Most participants were working or residing in nursing homes; mean age was 49 years. There was no difference in the risk of symptomatic confirmed COVID-19 or production of antibodies to SARS-CoV-2 between the two study arms. Authors' conclusions HCQ for people infected with COVID-19 has little or no effect on the risk of death and probably no effect on progression to mechanical ventilation. Adverse events are tripled compared to placebo, but very few serious adverse events were found. No further trials of hydroxychloroquine or chloroquine for treatment should be carried out. These results make it less likely that the drug is effective in protecting people from infection, although this is not excluded entirely. It is probably sensible to complete trials examining prevention of infection, and ensure these are carried out to a high standard to provide unambiguous results.
Izvorni podaci
- DOI
- 10.1002/14651858.cd013587.pub2
- PMID
- 33624299
- PMCID
- PMC8094389
- Provjereno
- 2026-07-26
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