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International Journal of... 2021Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses... (Review)
Review
Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the major pathogenic agents that cause number of serious diseases in humans, animals and plants. Viruses cause many diseases in humans, from self resolving diseases to acute fatal diseases. Developing strategies for the antiviral drugs are focused on two different approaches: Targeting the viruses themselves or the host cell factors. Antiviral drugs that directly target the viruses include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors, polymerase inhibitors, protease inhibitors, inhibitors of nucleoside and nucleotide reverse transcriptase and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and darunavir), viral DNA polymerase (acyclovir, tenofovir, valganciclovir and valacyclovir) and of integrase (raltegravir) are listed among the Top 200 Drugs by sales during 2010s. Still no effective antiviral drugs are available for many viral infections. Though, there are a couple of drugs for herpesviruses, many for influenza and some new antiviral drugs for treating hepatitis C infection and HIV. Action mechanism of antiviral drugs consists of its transformation to triphosphate following the viral DNA synthesis inhibition. An analysis of the action mechanism of known antiviral drugs concluded that they can increase the cell's resistance to a virus (interferons), suppress the virus adsorption in the cell or its diffusion into the cell and its deproteinisation process in the cell (amantadine) along with antimetabolites that causes the inhibition of nucleic acids synthesis. This review will address currently used antiviral drugs, mechanism of action and antiviral agents reported against COVID-19.
Topics: Animals; Antiviral Agents; COVID-19; Drug Therapy, Combination; Host-Pathogen Interactions; Humans; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33726557
DOI: 10.1177/20587384211002621 -
Acta Pharmaceutica Sinica. B Apr 2022HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure... (Review)
Review
HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.
PubMed: 35847492
DOI: 10.1016/j.apsb.2021.11.009 -
Stroke Oct 2021Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of... (Review)
Review
Certain drugs may increase the risk of ischemic stroke (IS). Our goal was to review associations between frequently used drugs and IS. We created an initial list of frequently used drugs to search Pubmed/MEDLINE from 1966 to 2020 and reviewed phase III and IV data, case series, and drug authorities' safety warnings to assess a potential association with IS. Drugs were grouped according to the World Health Organization Anatomical Therapeutic Chemical Classification System. Predefined criteria were applied to establish a level of evidence for an association, from A (high level of evidence of association) to E (high level of evidence of absence of association). In addition, we assessed relative risks and reviewed potential mechanisms of IS facilitation. We assessed 81 drugs or drug classes from 11 World Health Organization Anatomical Therapeutic Chemical Groups. We identified a high level of association for erythropoietin, combined contraceptives, oral estrogen replacement therapy, bevacizumab, tamoxifen, and antipsychotics and a moderate level for ponatinib, nilotinib, darunavir, and gonadotropin-releasing hormone agonists. Drug dose and treatment duration may modify the risk. For a substantial number of drugs, we found no association, and for others, there were insufficient data to categorize risk. We identified a high level of association of IS with a limited number of drugs, a potential association with some, and a lack of data for others. The summarized information may help clinicians to estimate the contribution of a drug to an IS, to better assess drug benefit-risk ratios, and to support decisions about using specific drugs.
Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Ischemic Stroke; Prescription Drugs
PubMed: 34404236
DOI: 10.1161/STROKEAHA.120.033272 -
The Lancet. HIV Jun 2022WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial.
BACKGROUND
WHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine.
METHODS
In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.
FINDINGS
Between July 30 and Dec 18, 2019, we screened 783 patients and enrolled 465. One participant was randomly assigned in error and immediately withdrawn. The remaining 464 participants were randomly assigned to receive either dolutegravir (n=235) or ritonavir-boosted darunavir (n=229) and to receive lamivudine plus either tenofovir (n=233) or zidovudine (n=231). At week 96, 211 (90%) of 235 participants in the dolutegravir group and 199 (87%) of 229 participants in the darunavir group had HIV-1 RNA less than 400 copies per mL (percentage point difference 2·9, 95% CI -3·0 to 8·7), indicating non-inferiority. Nine (4%) participants (all in the dolutegravir group) developed dolutegravir resistance; no participants developed darunavir resistance (p=0·0023). In the other randomised comparison, 214 (92%) of 233 patients in the tenofovir group and 196 (85%) of 231 patients in the zidovudine group had HIV-1 RNA less than 400 copies per mL (percentage point difference 7·0, 95% CI 1·2 to 12·8), showing non-inferiority and indicating the superiority of tenofovir (p=0·019). The proportions of participants with any grade 3-4 adverse event were similar between the dolutegravir (26 [11%]) and darunavir (28 [12%]) groups and between the tenofovir (22 [9%]) and zidovudine (32 [14%]) groups. There were no deaths related to study medication.
INTERPRETATION
Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks; dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy. Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine.
FUNDING
Janssen.
Topics: Anti-HIV Agents; Darunavir; Drug Therapy, Combination; HIV Infections; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Oxazines; Piperazines; Prospective Studies; Pyridones; RNA; Ritonavir; Tenofovir; Viral Load; Zidovudine
PubMed: 35460601
DOI: 10.1016/S2352-3018(22)00092-3 -
Current Opinion in HIV and AIDS Jan 2022We reviewed evidence concerning the novel nonnucleoside reverse transcriptase inhibitor doravirine, aiming to identify situations where it may be selected in preference... (Review)
Review
PURPOSE OF REVIEW
We reviewed evidence concerning the novel nonnucleoside reverse transcriptase inhibitor doravirine, aiming to identify situations where it may be selected in preference to integrase inhibitors.
RECENT FINDINGS
Doravirine is licenced for the treatment of HIV-1 in North America and Europe. In two multicentre randomized controlled trials, noninferiority with comparator drugs efavirenz and darunavir/ritonavir was observed at 96 weeks. Doravirine is associated with a lower incidence of neuropsychiatric side effects relative to efavirenz, and favourable lipid changes relative to darunavir over 96 weeks. A lower incidence of weight gain, relative to indirect comparisons with integrase inhibitors, was observed. Doravirine has a high genetic barrier to resistance with retained activity in the presence of single NNRTI mutations K103N, Y181C and G190A. Primary drug resistance is infrequent and may be higher in South Africa relative to European populations. Doravirine may be used in renal or hepatic impairment and has a low potential for drug-drug interactions.
SUMMARY
Doravirine is a well tolerated and effective agent in ART-naive patients. Direct comparison with integrase inhibitors, and evidence on the outcomes of treatment with doravirine in the presence of prior NNRTI experience are required to better elucidate which patients will benefit most from doravirine therapy.
Topics: Anti-HIV Agents; HIV Infections; Humans; Pyridones; Reverse Transcriptase Inhibitors; Triazoles
PubMed: 34740228
DOI: 10.1097/COH.0000000000000709 -
Profiles of Drug Substances,... 2021Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic... (Review)
Review
Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.
Topics: Darunavir; Drug Resistance, Viral; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Pregnancy; United States
PubMed: 33461696
DOI: 10.1016/bs.podrm.2020.07.001 -
AIDS (London, England) Jul 2021To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.
OBJECTIVE
To evaluate darunavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery.
DESIGN
Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of darunavir and cobicistat pharmacokinetics in pregnant women with HIV and their children in the United States.
METHODS
Intensive steady-state 24-h pharmacokinetic profiles were performed after administration of 800 mg of darunavir and 150 mg of cobicistat orally in fixed dose combination once-daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Darunavir and cobicistat were measured in plasma by validated HPLC-UV and liquid chromatography with tandem mass spectrometry detection (LC-MS)/MS assays, respectively. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons.
RESULTS
A total of 29 pregnant women receiving darunavir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, darunavir AUC0--24 was 53% lower in the second trimester [n = 12, P = 0.0024, geometric mean of ratio (GMR)=0.47, 90% confidence interval (CI) 0.33 - 0.68] and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.36 - 0.54), whereas cobicistat AUC0--24 was 50% lower in the second trimester (n = 12, P = 0.0024, GMR = 0.50, 90% CI 0.36-0.69) and 56% lower in the third trimester (n = 18, P < 0.0001, GMR = 0.44, 90% CI 0.35-0.55). Placental transfer of darunavir and cobicistat was limited.
CONCLUSION
Standard darunavir/cobicistat dosing during pregnancy results in significantly lower exposure during pregnancy, which may increase the risk of virologic failure and perinatal transmission.
Topics: Anti-HIV Agents; Child; Cobicistat; Darunavir; Female; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Placenta; Postpartum Period; Pregnancy; Prospective Studies
PubMed: 34076612
DOI: 10.1097/QAD.0000000000002857 -
Nature Communications Sep 2023Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral...
Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China.
Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.
Topics: Humans; Nevirapine; Cohort Studies; Lopinavir; Retrospective Studies; Benzoxazines; Acquired Immunodeficiency Syndrome; China
PubMed: 37660054
DOI: 10.1038/s41467-023-41051-w