ABSTRACT
HIV infection is one of the most acute problems of our time, characterized by slow development, prolonged course, and numerous clinical manifestations. Currently, there is a large number of drugs acting on different processes of human immunodeficiency virus replication, which constitute the group of highly active antiretroviral therapy (HAART). This article shows a theoretical review of modern HAART and analyzes the prescribed treatment regimens for patients with HIV infection. The study revealed two most common combinations: nucleoside reverse transcriptase inhibitors + protease inhibitors; nucleoside + non-nucleoside reverse transcriptase inhibitors.
Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections , Humans , HIV Infections/drug therapy , HIV Infections/virology , Anti-HIV Agents/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , HIV Protease Inhibitors/therapeutic useABSTRACT
INTRODUCTION: The amino acid substitution A62V in reverse transcriptase was identified as a mutation correlated with virologic failure in patients on first-line therapy including tenofovir (TDF) and tenofovir alafenamide (TAF). A62V is a typically polymorphic mutation in HIV-1 sub-subtype A6, which is the most widespread virus variant in Russia. MATERIALS AND METHODS: The European EuResist (EIDB) database was queried to form two equivalent groups of patients: group 1 â patients with A62V at baseline treated with TDF or TAF on the first-line therapy, group 2 â patients without A62V at baseline treated with TDF or TAF on the first-line therapy. Each group included 23 patients. RESULTS: There was no statistical difference between the two groups in virologic efficacy in 4, 12, and 24 weeks after the start of antiretroviral therapy (ART) and in the frequency of virologic failures. CONCLUSION: This study has some limitations, and the exact role of A62V in the efficacy of the first-line ART based on tenofovir deserves further investigation.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV Reverse Transcriptase , HIV-1 , Mutation , Tenofovir , Humans , Tenofovir/therapeutic use , Tenofovir/analogs & derivatives , HIV Infections/drug therapy , HIV Infections/virology , HIV Infections/genetics , HIV Reverse Transcriptase/genetics , HIV-1/genetics , HIV-1/drug effects , Male , Female , Adult , Anti-HIV Agents/therapeutic use , Middle Aged , Drug Resistance, Viral/genetics , Amino Acid Substitution , Alanine/therapeutic use , Russia/epidemiology , Adenine/analogs & derivatives , Adenine/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Viral Load/drug effectsABSTRACT
HIV-1 reverse transcriptase (RT) inhibitors play a crucial role in the treatment of HIV by preventing the activity of the enzyme responsible for the replication of the virus. The HIV-1 Tat protein binds to transactivation response (TAR) RNA and recruits host factors to stimulate HIV-1 transcription. We have created a small library consisting of 4 × 6 polypyridyl Ru(II) complexes that selectively bind to TAR RNA, with targeting groups specific to HIV-1 TAR RNA. The molecule design was conducted by introducing hydroxyl or methoxy groups into an established potent TAR binder. The potential TAR binding ability was analysis from nature charge population and electrostatic potential by quantum chemistry calculations. Key modifications were found to be R1 and R3 groups. The most potent and selective TAR RNA binder was a3 with R1 = OH, R2 = H and R3 = Me. Through molecular recognition of hydrogen bonds and electrostatic attraction, they were able to firmly and selectively bind HIV-1 TAR RNA. Furthermore, they efficiently obstructed the contact between TAR RNA and Tat protein, and inhibited the reverse transcription activity of HIV-1 RT. The polypyridyl Ru(II) complexes were chemical and photo-stable, and sensitive and selective spectroscopic responses to TAR RNA. They exhibited little toxicity towards normal cells. Hence, this study might offer significant drug design approaches for researching AIDS and other illnesses associated with RT, including HCV, EBOV, and SARS-CoV-2. Moreover, it could contribute to fundamental research on the interactions of inorganic transition metal complexes with biomolecules.
Subject(s)
Coordination Complexes , HIV Reverse Transcriptase , HIV-1 , RNA, Viral , Reverse Transcriptase Inhibitors , Ruthenium , Ruthenium/chemistry , HIV-1/drug effects , HIV-1/enzymology , Humans , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV Reverse Transcriptase/chemistry , Structure-Activity Relationship , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , RNA, Viral/metabolism , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemistry , HIV Long Terminal Repeat/drug effectsABSTRACT
Nucleoside reverse transcriptase inhibitors (NRTIs) have been extensively studied as drugs targeting HIV RT. However, the practice or use of approved NRTIs lacking the 3'-hydroxy group often promotes frequent HIV mutations and generates drug-resistance. Here, we describe a novel NRTI with 2'-ß-methylselenyl modification. We found that this modification inhibited the DNA elongation reaction by HIV-1 RT despite having a 3'-hydroxy group. Moreover, the conformation of this nucleoside analog is controlled at C3'-endo, a conformation that resists excision from the elongating DNA by HIV RT. Accordingly, the designed analogs exhibited activity against both wild-type HIV and multidrug-resistant HIV mutants.
Subject(s)
Anti-HIV Agents , HIV Reverse Transcriptase , HIV-1 , Mutation , Reverse Transcriptase Inhibitors , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/chemical synthesis , Humans , Structure-Activity Relationship , Molecular Structure , Nucleosides/chemistry , Nucleosides/pharmacology , Nucleosides/chemical synthesis , Microbial Sensitivity Tests , Dose-Response Relationship, DrugABSTRACT
While certain human hepatitis B virus-targeting nucleoside analogs (NAs) serve as crucial anti-HBV drugs, HBV yet remains to be a major global health threat. E-CFCP is a 4'-modified and fluoromethylenated NA that exhibits potent antiviral activity against both wild-type and drug-resistant HBVs but less potent against human immunodeficiency virus type-1 (HIV-1). Here, we show that HIV-1 with HBV-associated amino acid substitutions introduced into the RT's dNTP-binding site (N-site) is highly susceptible to E-CFCP. We determined the X-ray structures of HBV-associated HIV-1 RT mutants complexed with DNA:E-CFCP-triphosphate (E-CFCP-TP). The structures revealed that exocyclic fluoromethylene pushes the Met184 sidechain backward, and the resultant enlarged hydrophobic pocket accommodates both the fluoromethylene and 4'-cyano moiety of E-CFCP. Structural comparison with the DNA:dGTP/entecavir-triphosphate complex also indicated that the cyclopentene moiety of the bound E-CFCP-TP is slightly skewed and deviated. This positioning partly corresponds to that of the bound dNTP observed in the HIV-1 RT mutant with drug-resistant mutations F160M/M184V, resulting in the attenuation of the structural effects of F160M/M184V substitutions. These results expand our knowledge of the interactions between NAs and the RT N-site and should help further design antiviral NAs against both HIV-1 and HBV.
Subject(s)
Antiviral Agents , Catalytic Domain , Drug Resistance, Viral , HIV-1 , Hepatitis B virus , Mutation , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Drug Resistance, Viral/genetics , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , HIV-1/drug effects , HIV-1/genetics , Nucleosides/pharmacology , Nucleosides/chemistry , Nucleosides/metabolism , HIV Reverse Transcriptase/metabolism , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/metabolism , Crystallography, X-Ray , RNA-Directed DNA Polymerase/metabolism , RNA-Directed DNA Polymerase/genetics , RNA-Directed DNA Polymerase/chemistry , Binding Sites , Protein Binding , Models, MolecularABSTRACT
Starting from our previously reported nonnucleoside reverse transcriptase inhibitor (NNRTI, 3), continuous efforts were made to enhance its potency and safety through a structure-based drug design strategy. This led to the discovery of a series of novel piperidine-biphenyl-diarylpyrimidines (DAPYs). Compound 10p, the most active compound in this series, exhibited an EC50 value of 6 nM against wide-type HIV-1 strain, which was approximately 560-fold more potent than the initial compound 3 (EC50 = 3.36 µM). Furthermore, significant improvements were observed in cytotoxicity and selectivity (CC50 > 202.17 µM, SI > 33144) compared to compound 3 (CC50 = 14.84 µM, SI = 4). Additionally, compound 10p demonstrated increased inhibitory activity against clinically mutant virus strains (EC50 = 7-63 nM). Further toxicity evaluation revealed that compound 10p exhibited minimal CYP enzyme and hERG inhibition. Importantly, single-dose acute toxicity testing did not result in any fatalities or noticeable pathological damage in mice. Therefore, compound 10p can be regarded as a lead candidate for guiding further development of biphenyl-diarylpyrimidine NNRTIs with favorable druggability for HIV therapy.
Subject(s)
Anti-HIV Agents , Biphenyl Compounds , Drug Discovery , HIV Reverse Transcriptase , HIV-1 , Piperidines , Pyrimidines , Reverse Transcriptase Inhibitors , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Structure-Activity Relationship , Piperidines/chemistry , Piperidines/pharmacology , Piperidines/chemical synthesis , Humans , Biphenyl Compounds/pharmacology , Biphenyl Compounds/chemistry , Animals , HIV-1/drug effects , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/chemical synthesis , Mice , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Piperazines/chemistry , Piperazines/pharmacology , Piperazines/chemical synthesis , Piperazine/chemistry , Piperazine/pharmacologyABSTRACT
The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values < 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure-activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in the inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values~1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection.
Subject(s)
HIV Reverse Transcriptase , HIV-1 , Reverse Transcriptase Inhibitors , Thiazoles , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Humans , HIV-1/drug effects , HIV-1/enzymology , Thiazoles/pharmacology , Thiazoles/chemistry , Ribonuclease H/antagonists & inhibitors , Ribonuclease H/metabolism , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/chemical synthesis , Drug Discovery , Structure-Activity RelationshipABSTRACT
In the current antiretroviral landscape, continuous efforts are still needed to search for novel chemotypes of human immunodeficiency virus type 1 (HIV-1) inhibitors with improved drug resistance profiles and favorable drug-like properties. Herein, we report the design, synthesis, biological characterization, and druggability evaluation of a class of non-nucleoside reverse transcriptase inhibitors. Guided by the available crystallographic information, a series of novel indolylarylsulfone derivatives were rationally discovered via the substituent decorating strategy to fully explore the chemical space of the entrance channel. Among them, compound 11h bearing the cyano-substituted benzyl moiety proved to be the most effective inhibitor against HIV-1 wild-type and mutant strains (EC50 = 0.0039-0.338 µM), being far more potent than or comparable to etravirine and doravirine. Besides, 11h did not exhibit cytotoxicity at the maximum test concentration. Meanwhile, the binding target of 11h was further confirmed to be reverse transcriptase (IC50 = 0.055 µM). Preliminary structure-activity relationship were discussed to guide further optimization work. Molecular docking and dynamics simulation studies were investigated in detail to rationalize the biological evaluation results. Further drug-likeness assessment indicated that 11h possessed excellent physicochemical properties. Moreover, no apparent hERG blockade liability and cytochrome P450 inhibition were observed for 11h. Notably, 11h was characterized by favorable in vitro metabolic stability with moderate clearance rates and long half-lives in human plasma and liver microsomes. Overall, 11h holds great promise as an ideal Anti-HIV-1 lead compound due to its potent antiviral efficacy, low toxicity, and favorable drug-like profiles.
Subject(s)
Anti-HIV Agents , Drug Design , HIV-1 , Molecular Docking Simulation , Reverse Transcriptase Inhibitors , Sulfones , HIV-1/drug effects , Humans , Anti-HIV Agents/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Structure-Activity Relationship , Sulfones/pharmacology , Sulfones/chemical synthesis , Sulfones/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolismABSTRACT
Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context.
Subject(s)
Aflatoxin B1 , Alkynes , Benzoxazines , Cyclopropanes , Drug Interactions , Microsomes, Liver , Models, Biological , Reverse Transcriptase Inhibitors , Aflatoxin B1/pharmacokinetics , Aflatoxin B1/toxicity , Humans , Benzoxazines/pharmacokinetics , Benzoxazines/metabolism , Microsomes, Liver/metabolism , Microsomes, Liver/drug effects , Reverse Transcriptase Inhibitors/pharmacokinetics , Male , Cytochrome P-450 CYP3A/metabolism , Adult , Female , Cytochrome P-450 CYP1A2/metabolism , Middle Aged , Young Adult , White PeopleABSTRACT
Islatravir (ISL) is a deoxyadenosine analog that inhibits HIV-1 reverse transcription by multiple mechanisms. Lenacapavir (LEN) is a novel capsid inhibitor that inhibits HIV-1 at multiple stages throughout the viral life cycle. ISL and LEN are being investigated as once-weekly combination oral therapy for the treatment of HIV-1. Here, we characterized ISL and LEN in vitro to assess combinatorial antiviral activity, cytotoxicity, and the potential for interactions between the two compounds. Bliss analysis revealed ISL with LEN demonstrated additive inhibition of HIV-1 replication, with no evidence of antagonism across the range of concentrations tested. ISL exhibited potent antiviral activity against variants encoding known LEN resistance-associated mutations (RAMs) with or without the presence of M184V, an ISL RAM in reverse transcriptase (RT) . Static resistance selection experiments were conducted with ISL and LEN alone and in combination, initiating with either wild-type virus or virus containing the M184I RAM in RT to further assess their barrier to the emergence of resistance. The combination of ISL with LEN more effectively suppressed viral breakthrough at lower multiples of the compounds' IC50 (half-maximal inhibitory concentration) values and fewer mutations emerged with the combination compared to either compound on its own. The known pathways for development of resistance with ISL and LEN were not altered, and no novel single mutations emerged that substantially reduced susceptibility to either compound. The lack of antagonism and cross-resistance between ISL and LEN support the ongoing evaluation of the combination for treatment of HIV-1.
Subject(s)
Anti-HIV Agents , Drug Resistance, Viral , HIV-1 , Virus Replication , HIV-1/drug effects , HIV-1/genetics , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Humans , Anti-HIV Agents/pharmacology , Virus Replication/drug effects , Deoxyadenosines/pharmacology , Mutation , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/genetics , Reverse Transcriptase Inhibitors/pharmacology , Microbial Sensitivity Tests , Cell Line , HIV Infections/drug therapy , HIV Infections/virologyABSTRACT
HIV infection has been controlled only since the introduction of triple therapy in 1996, combining, as antiretroviral agents, two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor (PI). However, among the NRTIs, the thymidine analogues stavudine and zidovudine led to lipoatrophy, either generalized or associated with visceral fat hypertrophy and buffalo hump. These molecules also increased insulin resistance and the prevalence of diabetes. They were replaced by other NRTIs or non-NRTIs (NNRTIs) that were considered to be free of adipose tissue (AT) toxicity. More recently, the NRTI tenofovir disoproxyfumarate (TDF) and the NNRTI efavirenz have been associated with inhibition of fat gain but not with clear lipoatrophy. Otherwise, the use of PIs led to a phenotype of trunk fat hypertrophy associated with cardiometabolic complications. To avoid their adverse effects, PIs have recently been replaced by a new class of antiretrovirals, the integrase inhibitors (INSTIs), which are well tolerated and effective in controlling HIV. However, this class has been associated with global weight gain, which may be important and concerning for some people living with HIV (PWH). Also, in the NRTI class, TDF has often been replaced by tenofovir alafenamide (TAF) due to bone and renal toxicities, and TAF has been associated with global fat gain. The cardiometabolic consequences of INTIs and TAF are primarily related to the associated weight gain. In the global obesogenic worldwide context, PWH are gaining weight as well in relation to poor health life conditions. Taking in charge obesity uses the same strategies as those used in the general population.
Subject(s)
Adipose Tissue , HIV Infections , Humans , HIV Infections/drug therapy , Adipose Tissue/drug effects , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , HIV-Associated Lipodystrophy Syndrome/chemically induced , Anti-Retroviral Agents/adverse effects , Anti-Retroviral Agents/therapeutic use , Tenofovir/therapeutic use , Tenofovir/adverse effectsABSTRACT
To enhance the DNA/RNA amplification efficiency and inhibitor tolerance of Bst DNA polymerase, four chimeric Bst DNA polymerase by fusing with a DNA-binding protein Sto7d and/or a highly hydrophobic protein Hp47 to Bst DNA polymerase large fragment. One of chimeric protein HpStBL exhibited highest inhibitor tolerance, which retained high active under 0.1 U/µL sodium heparin, 0.8 ng/µL humic acid, 2.5× SYBR Green I, 8 % (v/v) whole blood, 20 % (v/v) tissue, and 2.5 % (v/v) stool. Meanwhile, HpStBL showed highest sensitivity (93.75 %) to crude whole blood infected with the African swine fever virus. Moreover, HpStBL showed excellent reverse transcriptase activity in reverse transcription loop-mediated isothermal amplification, which could successfully detect 0.5 pg/µL severe acute respiratory syndrome coronavirus 2 RNA in the presence of 1 % (v/v) stools. The fusion of two domains with different functions to Bst DNA polymerase would be an effective strategy to improve Bst DNA polymerase performance in direct loop-mediated isothermal amplification and reverse transcription loop-mediated isothermal amplification detection, and HpStBL would be a promising DNA polymerase for direct African swine fever virus/severe acute respiratory syndrome coronavirus 2 detection due to simultaneously increased inhibitor tolerance and reverse transcriptase activity.
Subject(s)
African Swine Fever Virus , RNA-Directed DNA Polymerase , RNA-Directed DNA Polymerase/metabolism , RNA-Directed DNA Polymerase/genetics , African Swine Fever Virus/genetics , African Swine Fever Virus/enzymology , Animals , Recombinant Fusion Proteins/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Swine , Nucleic Acid Amplification Techniques/methods , Protein Domains , DNA-Directed DNA Polymerase/genetics , DNA-Directed DNA Polymerase/metabolism , Reverse Transcriptase Inhibitors/pharmacology , COVID-19/virology , RNA, Viral/geneticsABSTRACT
Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) (n = 109) or tenofovir/emtricitabine (TFV/3TC) (n = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI95, 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); P = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI95, 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens.
Subject(s)
Anti-HIV Agents , HIV Infections , Lamivudine , Pyridones , Triazoles , Humans , HIV Infections/drug therapy , HIV Infections/virology , Female , Pyridones/adverse effects , Male , Adult , Middle Aged , Lamivudine/therapeutic use , Lamivudine/adverse effects , Lamivudine/administration & dosage , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/adverse effects , Anti-HIV Agents/administration & dosage , Triazoles/therapeutic use , Triazoles/adverse effects , Triazoles/administration & dosage , Dideoxynucleosides/therapeutic use , Dideoxynucleosides/adverse effects , Dideoxynucleosides/administration & dosage , Drug Combinations , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/administration & dosage , Oxazines/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/adverse effects , Spain , Treatment Outcome , Cobicistat/therapeutic use , Cobicistat/adverse effects , Cobicistat/administration & dosage , Darunavir/therapeutic use , Darunavir/adverse effects , Piperazines/adverse effects , Viral Load/drug effects , HIV-1/drug effects , HIV-1/genetics , Cyclopropanes , Dideoxyadenosine/analogs & derivativesABSTRACT
As a typical RNA virus, the genetic information on HIV-1 is entirely stored in RNA. The reverse transcription activity of HIV-1 reverse transcriptase (RT) plays a crucial role in the replication and transmission of the virus. Non-nucleoside RT inhibitors (NNRTIs) block the function of RT by binding to the RNA binding site on RT, with very few targeting viral RNA. In this study, by transforming planar conjugated ligands into a spiro structure, we convert classical Ru(II) DNA intercalators into a nonintercalator. This enables selective binding to HIV-1 transactivation response (TAR) RNA on the outer side of nucleic acids through dual interactions involving hydrogen bonds and electrostatic attraction, effectively inhibiting HIV-1 RT and serving as a selective fluorescence probe for TAR RNA.
Subject(s)
HIV Reverse Transcriptase , HIV-1 , Reverse Transcriptase Inhibitors , Ruthenium , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/metabolism , Ligands , HIV-1/enzymology , HIV-1/drug effects , Ruthenium/chemistry , Ruthenium/pharmacology , RNA, Viral/metabolism , RNA, Viral/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/metabolism , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Molecular Structure , Humans , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Long Terminal Repeat , Binding SitesABSTRACT
OBJECTIVE: Integrase strand transfer inhibitors (INSTI) are associated with weight gain in people with HIV (PWH), but their impact on diabetes is unclear. We evaluated the association between switching from nonnucleoside reverse-transcriptase inhibitors (NNRTI) or protease inhibitors (PI) to INSTI and incident diabetes. DESIGN: Longitudinal cohort study. METHODS: We included PWH aged ≥18âyears from the Johns Hopkins HIV Clinical Cohort (2007-2023) without history of diabetes who had used NNRTI or PI for ≥180âdays. We followed participants up to 10âyears from HIV primary care visits where they switched to INSTI or continued NNRTI or PI. We estimated the hazard of incident diabetes associated with switching to INSTI using weighted Cox regression with robust variance estimator. RESULTS: We included 2075 PWH who attended 22 116 visits where they continued NNRTI or PI and 631 visits where they switched to INSTI. Switching to INSTI was associated with a weighted hazard ratio (wHR) of 1.11 [95% confidence interval (CI), 0.77-1.59] for incident diabetes. The association if no weight gain occurred during the first two years was not qualitatively different (wHR 1.22; 95% CI, 0.82-1.80). In a posthoc analysis, switching to INSTI conferred a significant wHR of 1.79 (95% CI, 1.13-2.84) for diabetes within the first two years but not after. CONCLUSIONS: Switching from NNRTI or PI to INSTI did not significantly increase overall diabetes incidence in PWH, although there may be elevated risk in the first two years. These findings can inform considerations when switching to INSTI-based regimens.
Subject(s)
Diabetes Mellitus , HIV Infections , HIV Integrase Inhibitors , Humans , Male , HIV Infections/drug therapy , HIV Infections/complications , Female , Adult , Middle Aged , Longitudinal Studies , Diabetes Mellitus/epidemiology , HIV Integrase Inhibitors/therapeutic use , HIV Integrase Inhibitors/adverse effects , Incidence , Drug Substitution/statistics & numerical data , Weight Gain , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic useABSTRACT
Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure-activity relationships (SAR). We found the correlation between IC50s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC50 of 0.030 µM ± 0.009. This compared to FIV IC50 values of 0.22 ± 0.17 µM, 0.040 ± 0.010 µM and >160 µM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.
Subject(s)
HIV Reverse Transcriptase , Immunodeficiency Virus, Feline , Reverse Transcriptase Inhibitors , Animals , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Cats , Immunodeficiency Virus, Feline/drug effects , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , Humans , Structure-Activity Relationship , Pyrimidines/chemistry , Pyrimidines/pharmacology , Alkynes/chemistry , Alkynes/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Cyclopropanes/pharmacology , Cyclopropanes/chemistry , Molecular Docking Simulation , Benzoxazines/chemistry , Benzoxazines/pharmacologyABSTRACT
Reducing neuroinflammation, a key contributor to brain aging and neurodegenerative diseases, is a promising strategy for improving cognitive function in these settings. The FDA-approved nucleoside reverse transcriptase inhibitor 3TC (Lamivudine) has been reported to improve cognitive function in old wild-type mice and multiple mouse models of neurodegenerative disease, but its effects on the brain have not been comprehensively investigated. In the current study, we used transcriptomics to broadly characterize the effects of long-term supplementation with a human-equivalent therapeutic dose of 3TC on the hippocampal transcriptome in male and female rTg4510 mice (a commonly studied model of tauopathy-associated neurodegeneration). We found that tauopathy increased hippocampal transcriptomic signatures of neuroinflammation/immune activation, but 3TC treatment reversed some of these effects. We also found that 3TC mitigated tauopathy-associated activation of key transcription factors that contribute to neuroinflammation and immune activation, and these changes were related to improved recognition memory performance. Collectively, our findings suggest that 3TC exerts protective effects against tauopathy in the hippocampus by modulating inflammation and immune activation, and they may provide helpful insight for ongoing clinical efforts to determine if 3TC and/or related therapeutics hold promise for treating neurodegeneration.
Subject(s)
Disease Models, Animal , Hippocampus , Lamivudine , Reverse Transcriptase Inhibitors , Tauopathies , Transcriptome , Animals , Hippocampus/metabolism , Hippocampus/drug effects , Tauopathies/drug therapy , Tauopathies/genetics , Mice , Male , Reverse Transcriptase Inhibitors/pharmacology , Female , Lamivudine/pharmacology , Lamivudine/therapeutic use , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/genetics , Mice, Transgenic , Inflammation/drug therapyABSTRACT
BACKGROUND: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. METHODS: D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. FINDINGS: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per µL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. INTERPRETATION: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. FUNDING: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.
Subject(s)
Darunavir , HIV Infections , HIV-1 , Heterocyclic Compounds, 3-Ring , Oxazines , Piperazines , Pyridones , Reverse Transcriptase Inhibitors , Ritonavir , Viral Load , Humans , Darunavir/therapeutic use , Darunavir/administration & dosage , HIV Infections/drug therapy , HIV Infections/virology , Female , Adult , Male , HIV-1/drug effects , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Viral Load/drug effects , Middle Aged , Reverse Transcriptase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/administration & dosage , Ritonavir/therapeutic use , Ritonavir/administration & dosage , Standard of Care , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , Drug Therapy, Combination , Emtricitabine/therapeutic use , Emtricitabine/administration & dosage , Treatment Outcome , Antiretroviral Therapy, Highly Active , Tenofovir/therapeutic use , Tenofovir/administration & dosage , CD4 Lymphocyte Count , Treatment Failure , Lamivudine/therapeutic use , Lamivudine/administration & dosageABSTRACT
In China, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are integral to the antiretroviral therapy (ART) regimen for persons living with HIV (PWH), comprising over 80% of such treatments. To broaden treatment options and improve therapeutic effectiveness, Ainuovirine (ANV), a new NNRTI, was authorized for ART in 2021. Nevertheless, the clinical efficacy of ANV and its impact on blood biochemical markers remain somewhat underexplored. This study seeks to evaluate ANV's clinical performance in ART and its influence on relevant treatment parameters. A retrospective analysis was performed on 208 patients treated with an ANV-based regimen from July 2021 to July 2023, monitoring indicator changes from baseline to week 24. The primary endpoint was the proportion of participants achieving HIV-1 RNA levels of less than 50 copies/mL by week 24. Secondary endpoints involved assessing variations in CD4+ T cell counts and blood biochemical markers from baseline. These outcomes were also compared with data from 241 patients treated with an Efavirenz (EFV)-based regimen in the same time frame. The findings suggest that the ANV-based regimen is as effective as the EFV-based regimen in viral suppression (p > .05) and offers superior improvements in lipid profiles, liver function, and immune system indicators, alongside fewer adverse reactions. These results affirm ANV's efficacy and safety as an antiretroviral therapy option, offering Acquired Immune Deficiency Syndrome patients a wider array of treatment possibilities and the potential for better treatment outcomes.
Subject(s)
Alkynes , Anti-HIV Agents , Benzoxazines , Cyclopropanes , HIV Infections , Humans , HIV Infections/drug therapy , Male , Benzoxazines/therapeutic use , Benzoxazines/adverse effects , Cyclopropanes/therapeutic use , Alkynes/therapeutic use , Female , China , Adult , Retrospective Studies , Middle Aged , CD4 Lymphocyte Count , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/adverse effects , Viral Load/drug effects , Treatment Outcome , HIV-1/drug effects , Reverse Transcriptase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/adverse effects , RNA, Viral/blood , Antiretroviral Therapy, Highly Active/adverse effects , Antiretroviral Therapy, Highly Active/methodsABSTRACT
OBJECTIVE: To investigate the characteristics of drug resistance mutations (DRMs) and their contextual influence on drug susceptibility in CRF07_BC and CRF_08BC subtypes. METHODS: Patients with virological failure were genotyped using phylogenetic analysis. DRMs and susceptibility to antiretroviral drugs were analysed using the Stanford University HIV Drug Resistance Database. RESULTS: Six HIV subtypes were identified among 1296 successfully amplified sequences, with the CRF07_BC subtype prevailing at a rate of 91.7%, followed by CRF08_BC. Overall, the CRF07_BC and CRF08_BC subtypes were similar in the distribution and frequency of DRMs, the most common DRMs were K103N and M184V. However, among patients with antiretroviral therapy duration of ≥3 y who developed resistance, CRF08_BC exhibited a higher mutation frequency at sites 184, 138, 221, and 188 (Chi-square test, P < 0.05), and compared with CRF07_BC, patients with CRF08_BC had higher prevalence of abacavir, emtricitabine, lamivudine, doravirine, etravirine, and rilpivirine resistance. Moreover, there was an increased prevalence of cross-resistance between efavirenz/nevirapine and new-generation NNRTIs in patients with CRF08_BC; doravirine (r = 1.0), rilpivirine (r = 0.93), and etravirine (r = 0.86) resistance highly correlated with efavirenz/nevirapine. CONCLUSIONS: The present study provides valuable insights into the profile of DRMs and resistance patterns in patients with CRF07_BC and CRF08_BC experiencing treatment failure in Butuo. These findings have the potential to contribute to future strategies for HIV control and treatment.