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Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial.

ABSTRACT: Favipiravir (FVP), lopinavir/ritonavir (LPV/RTV), and interferon-beta (INF-beta) are considered as potential treatments for COVID-19. We examined the efficacy and safety of FVP and INF-beta compared to LPV/RTV and INF-beta combinations for the treatment of SARS-CoV-2. It was a single-center randomized clinical trial. Eligible patients were randomized to receive FVP plus INF-beta versus LPV/RTV plus INF-beta. The primary endpoint was the viral clearance after seven days of randomization. ICU admission, length of stay (LOS) in hospital, in-hospital mortality, and the incidence of adverse events were also measured. This trial was registered on the Iranian Registry of Clinical Trials (IRCT20200506047323N3). Patients were randomly allocated to the FVP (n = 33) and LPV/RTV (n = 33) groups. The viral clearance on Day seven was not significantly different between the FVP (31.1%) and the LPV/RTV groups (16.1%). The rate of ICU admission and likewise the in-hospital mortality in the FVP group (12.5% and 6.3%, respectively) were similar to the LPV/RTV groups (19.4% and 19.4%, respectively). The median LOS in the hospital was also not different (6.8 days [interquartile range; IQR = 5.0-11.0] in the FVP and (8.0 days [IQR = 5.5-12.5]) in LPV/RTV groups (p = 0.140). Adverse events were observed in 25.0% of FVP and 32.3% of LPV/RTV groups. The combination therapy with FVP did not exert a higher efficacy compared to the combination regimen of LPV/RTV. However, both treatment regimens demonstrated a mild profile of adverse events.

SUBMITTER: Hassaniazad M

PROVIDER: S-EPMC9088571 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesWe will evaluate the efficacy and safety of favipiravir and interferon beta-1a compared to lopinavir/ritonavir and interferon beta-1a in patients with confirmed COVID-19, who are moderately ill.Trial designThis is a phase 3, single-center, randomized, open-label, controlled trial with a parallel-group design carried out at Shahid Mohammadi Hospital, Bandar Abbas, Iran.ParticipantsAll patients with age ≥ 20 years admitted at the Severe Acute Respiratory Syndrome Departments of the Shahid Mohammadi Hospital, Bandar Abbas, Iran, will be screened for the following criteria.Inclusion criteria1. Confirmed diagnosis of infection with SARS-CoV-2 using polymerase chain reaction and/or antibody tests. 2. Moderate COVID-19 pneumonia (via computed tomography and/or X-ray imaging), requiring hospitalization. 3. Hospitalized ≤ 48 h. 4. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm.Exclusion criteria1. Underlying conditions, including chronic hepatitis, cirrhosis, cholestatic liver diseases, cholecystitis, peptic ulcers, acute and chronic renal failure, and peptic ulcers. 2. Severe and critical COVID-19 pneumonia. 3. History of allergy to favipiravir, lopinavir/ritonavir, and interferon beta-1a. 4. Pregnancy and breastfeeding.Intervention and comparatorIntervention group: favipiravir (Zhejiang Hisun, China) with interferon beta-1a (CinnaGen, Iran). This group will receive 1600 mg favipiravir twice a day for the first day and 600 mg twice a day for the following 4 days with five doses of 44 mcg interferon beta-1a every other day.Control grouplopinavir/ritonavir (Heterd Company, India) with interferon beta-1a (CinnaGen, Iran). This group will receive 200/50 mg lopinavir/ritonavir twice a day for 7 days with five doses of 44 mcg interferon beta-1a every other day. Other supportive and routine care will be the same in both groups.Main outcomesThe primary outcome of the trial is the viral load of SARS-CoV-2 in the nasopharyngeal samples assessed by RT-PCR after 7 days of randomization as well as clinical improvement of fever and O2 saturation within 7 days of randomization. The secondary outcomes are the length of hospital stay and the incidence of serious adverse drug reactions within 7 days of randomization.RandomizationEligible patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). A web-based system will be used to generate random numbers for the allocation sequence. Each number relates to one of the study arms.Blinding (masking)This is an open-label trial without blinding and placebo control.Numbers to be randomized (sample size)A total of 60 patients will be randomized into two groups (30 patients in the intervention group and 30 patients in the control group).Trial statusThe trial protocol is version 1.0, 22 July 2020. Recruitment began on 25 July 2020 and is anticipated to be completed by 25 September 2020.Trial registrationIranian Registry of Clinical Trials (IRCT) IRCT20200506047323N3 . Registered on 22 July 2020.Full protocolThe full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Project description:ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.MethodsWe conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.ResultsThe intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

Project description:BackgroundNevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established.MethodsIn a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24.ResultsA total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06).ConclusionsOutcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Project description:BackgroundAlbuvirtide (ABT), a fusion inhibitor against human immunodeficiency virus (HIV) infection, has good efficacy and tolerability for HIV treatment. However, there is a paucity of data regarding ABT-based regimen as second-line therapy. This current study evaluated the efficacy and safety of switching to ABT + ritonavir-boosted lopinavir (LPV/r) treatment in a cohort of HIV-infected individuals who failed initial treatment.MethodsThis retrospective comparative cohort study included patients who failed initial treatment and switched to either ABT + LPV/r (the ABT group) or two nucleotide reverse transcriptase inhibitors (NRTIs) + LPV/r (the NRTI group) between November 2019 and December 2020 in the People's Hospital of Zhaojue County in Liangshan Yi Autonomous Prefecture, China. All individuals were followed up from baseline to 12 weeks after conversion, or until the patient developed unacceptable toxic effects or was loss of follow-up. The proportion of patients who achieved virological suppression (viral load <50 copies/mL) at week 12 was considered a primary efficacy endpoint. Safety outcomes included the incidence of adverse events and laboratory abnormalities. All participants underwent resistance testing before regimen conversion. The linear regression model was applied to evaluate the association of CD4+ T cell count with the patient's clinical characteristics.ResultsA total of 71 patients were included in this study, the two groups were comparable at baseline in terms of age, sex, CD4+ T cell count, and viral load. The suppression of HIV-1 RNA to levels <50 copies/mL was achieved in 82.4% (28/31) and 29.7% (11/34) of patients in the ABT group and the NRTI group, respectively (P<0.001). Older age (P=0.016) and higher alkaline phosphatase (ALP) levels (P=0.038), but not rescue regimen, were associated with attenuated CD4+ T cell recovery. Most adverse events mild in severity, with abdominal pain as the most reported event in two groups (26.8%, 19/71), and no severe adverse events were detected.ConclusionsConversion to ABT + LPV/r therapy appears to be an effective and safe strategy. This treatment regimen has great potential to be generalized in the HIV-infected population, although further testing in a larger patient population is required to verify these results.

Project description:We sought to evaluate the effects of antiretroviral therapy on skeletal metabolism in Chinese individuals with human immunodeficiency virus. Patients switched to tenofovir/lamivudine + lopinavir/ritonavir after treatment failure had an increase in bone resorption marker levels by nearly 60%, which is greater than the magnitude previously described in non-Chinese populations.Few studies have evaluated the effects of antiretroviral therapy on skeletal metabolism in Asian populations infected with human immunodeficiency virus (HIV).We performed a secondary analysis of bone turnover markers (BTM) at baseline and 2 years in stored plasma samples collected from 2/2009 to 1/2013 as part of a multi-center trial. Two groups were compared: (1) treatment-naïve patients initiated on zidovudine (AZT)/lamivudine (3TC) plus nevirapine (NVP) and (2) patients who failed first-line therapy and were switched to tenofovir (TDF)/3TC plus lopinavir/ritonavir (LPVr). Tests included the bone resorption marker, C-terminal cross-linking telopeptide of type-1 collagen (CTX), and the bone formation marker procollagen type 1 N-terminal propeptide (P1NP).In the TDF/3TC?+?LPVr group, samples were available from 59 patients at baseline and 56 patients at 2 years. Of these, 36 patients had samples available from both time points. In the AZT/3TC?+?NVP group, plasma samples were analyzed from 82 participants at baseline and of those, 61 had samples at 2 years. Median change over 2 years was greater in the TDF/3TC?+?LPVr group for both CTX (+0.24 ng/mL, interquartile ranges (IQR) 0.10-0.43 vs. +0.09 ng/mL, IQR -0.03 to 0.18, p = 0.001) and P1NP (+25.5 ng/mL, IQR 2.4-51.3 vs. +7.11 ng/mL, IQR -4.3 to 21.6, p = 0.012). Differences remained after adjusting for potential confounders in the multivariable analysis.Switching to TDF/3TC?+?LPVr after treatment failure resulted in greater increases in BTMs than initiation with AZT/3TC?+?NVP in Chinese patients with HIV. Following this change, bone resorption marker levels increased by nearly 60 %, which is greater than the 25-35% increase from baseline described previously in non-Chinese populations. Further studies are warranted to elucidate these findings.

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Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial.

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