Journal articles: 'Nucleos(t)ide inhibitors (NI)'

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von Hentig, Nils. "Repositioning HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors for the treatment of SARS-CoV-2 infection and COVID-19." European Journal of Clinical Pharmacology 77, no. 9 (March 4, 2021): 1297–307. http://dx.doi.org/10.1007/s00228-021-03108-x.

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Abstract Aims SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. Subject and method SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. Results Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. Discussion This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.

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Novotny, Laura A., John Grayson Evans, Lishan Su, Haitao Guo, and Eric G. Meissner. "Review of Lambda Interferons in Hepatitis B Virus Infection: Outcomes and Therapeutic Strategies." Viruses 13, no. 6 (June 9, 2021): 1090. http://dx.doi.org/10.3390/v13061090.

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Hepatitis B virus (HBV) chronically infects over 250 million people worldwide and causes nearly 1 million deaths per year due to cirrhosis and liver cancer. Approved treatments for chronic infection include injectable type-I interferons and nucleos(t)ide reverse transcriptase inhibitors. A small minority of patients achieve seroclearance after treatment with type-I interferons, defined as sustained absence of detectable HBV DNA and surface antigen (HBsAg) antigenemia. However, type-I interferons cause significant side effects, are costly, must be administered for months, and most patients have viral rebound or non-response. Nucleos(t)ide reverse transcriptase inhibitors reduce HBV viral load and improve liver-related outcomes, but do not lower HBsAg levels or impart seroclearance. Thus, new therapeutics are urgently needed. Lambda interferons (IFNLs) have been tested as an alternative strategy to stimulate host antiviral pathways to treat HBV infection. IFNLs comprise an evolutionarily conserved innate immune pathway and have cell-type specific activity on hepatocytes, other epithelial cells found at mucosal surfaces, and some immune cells due to restricted cellular expression of the IFNL receptor. This article will review work that examined expression of IFNLs during acute and chronic HBV infection, the impact of IFNLs on HBV replication in vitro and in vivo, the association of polymorphisms in IFNL genes with clinical outcomes, and the therapeutic evaluation of IFNLs for the treatment of chronic HBV infection.

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Shin, Hye, Chonsaeng Kim, and Sungchan Cho. "Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are Broad-Spectrum Antiviral Drugs that Activate Innate Immunity." Viruses 10, no. 4 (April 20, 2018): 211. http://dx.doi.org/10.3390/v10040211.

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Baker, Jennifer, Petrie M. Rainey, David E. Moody, Gene D. Morse, Qing Ma, and Elinore F. McCance-Katz. "Interactions between Buprenorphine and Antiretrovirals: Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTI) Didanosine, Lamivudine, and Tenofovir." American Journal on Addictions 19, no. 1 (January 2010): 17–29. http://dx.doi.org/10.1111/j.1521-0391.2009.00004.x.

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Soriano, Vicente, Pablo Barreiro, Edward Cachay, Shyamasundaran Kottilil, José V. Fernandez-Montero, and Carmen de Mendoza. "Advances in hepatitis B therapeutics." Therapeutic Advances in Infectious Disease 7 (January 2020): 204993612096502. http://dx.doi.org/10.1177/2049936120965027.

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Despite the availability of both effective preventive vaccines and oral antivirals, over 250 million people are chronically infected with the hepatitis B virus (HBV). Globally, chronic hepatitis B is the leading cause of hepatocellular carcinoma, which represents the third cause of cancer mortality, accounting for nearly 1 million annual deaths. Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss. Thus, treatment has to be given lifelong to prevent viral rebound. A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors. Some of them exhibit higher potency than current oral nucleos(t)ides. Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731, ARO-HBV and REP-2139. To date, only treatment with ARO-HBV and with REP-2139 have resulted in HBsAg loss in a significant proportion of patients. Combination therapies using distinct antivirals and/or immune modulators are expected to maximize treatment benefits. The current goal is to achieve a ‘functional cure’, with sustained serum HBsAg after drug discontinuation. Ultimately, the goal of HBV therapy will be virus eradication, an achievement that would require the elimination of the cccDNA reservoir within infected hepatocytes.

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Prifti, Georgia-Myrto, Dimitrios Moianos, Erofili Giannakopoulou, Vasiliki Pardali, John Tavis, and Grigoris Zoidis. "Recent Advances in Hepatitis B Treatment." Pharmaceuticals 14, no. 5 (May 1, 2021): 417. http://dx.doi.org/10.3390/ph14050417.

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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Ireland, Peter J., John E. Tavis, Michael P. D'Erasmo, Danielle R. Hirsch, Ryan P. Murelli, Mark M. Cadiz, Bindi S. Patel, et al. "Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses." Antimicrobial Agents and Chemotherapy 60, no. 4 (January 19, 2016): 2140–49. http://dx.doi.org/10.1128/aac.02675-15.

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ABSTRACTHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compounds inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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Borghetti, Alberto, Gianmaria Baldin, Amedeo Capetti, Gaetana Sterrantino, Stefano Rusconi, Alessandra Latini, Andrea Giacometti, et al. "Efficacy and tolerability of dolutegravir and two nucleos(t)ide reverse transcriptase inhibitors in HIV-1-positive, virologically suppressed patients." AIDS 31, no. 3 (January 2017): 457–59. http://dx.doi.org/10.1097/qad.0000000000001357.

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Montejano, Rocio, Natalia Stella-Ascariz, Susana Monge, José I. Bernardino, Ignacio Pérez-Valero, Maria Luisa Montes, Eulalia Valencia, et al. "Impact of Nucleos(t)ide Reverse Transcriptase Inhibitors on Blood Telomere Length Changes in a Prospective Cohort of Aviremic HIV–Infected Adults." Journal of Infectious Diseases 218, no. 10 (June 15, 2018): 1531–40. http://dx.doi.org/10.1093/infdis/jiy364.

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Ohsaki, Eriko, Yadarat Suwanmanee, and Keiji Ueda. "Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy." Viruses 13, no. 9 (August 26, 2021): 1691. http://dx.doi.org/10.3390/v13091691.

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Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection.

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Elmessaoudi-Idrissi, Mohcine, Arnaud Blondel, Anass Kettani, Marc P. Windisch, Soumaya Benjelloun, and Sayeh Ezzikouri. "Virtual Screening in Hepatitis B Virus Drug Discovery: Current Stateof- the-Art and Future Perspectives." Current Medicinal Chemistry 25, no. 23 (July 4, 2018): 2709–21. http://dx.doi.org/10.2174/0929867325666180221141451.

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Hepatitis B Virus (HBV) is a major global health burden. Interferon alpha and nucleos(t)ide analogues are currently the standard-of-care for chronic HBV infection. However, these antiviral agents have limited efficacy and do not result in a sustained virological response in the majority of infected patients. Virtual Screening (VS) strategies have now a strong impact on drug discovery, the strength of this research field has been corroborated by recent contributions in the development of novel drug candidates which are in clinical trials or which are already available in the clinics. In this context, different VS strategies have been applied to HBV in order to discover novel inhibitors. In this review, we summarize the VS efforts to identify and design novel HBV interventions. We believe that the combination of in silico and in vitro tools can lead to faster validation of novel drug targets which could accelerate the HBV drug discovery and development efforts.

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Fourati, Slim, Benoit Visseaux, Daniele Armenia, Laurence Morand-Joubert, Anna Artese, Charlotte Charpentier, Peter Van Den Eede, et al. "Identification of a rare mutation at reverse transcriptase Lys65 (K65E) in HIV-1-infected patients failing on nucleos(t)ide reverse transcriptase inhibitors." Journal of Antimicrobial Chemotherapy 68, no. 10 (June 7, 2013): 2199–204. http://dx.doi.org/10.1093/jac/dkt200.

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Hollenbaugh, Joseph A., Susan M. Schader, Raymond F. Schinazi, and Baek Kim. "Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4+ T cells." Virology 485 (November 2015): 313–21. http://dx.doi.org/10.1016/j.virol.2015.08.006.

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Blanco, José L., Ana Gonzalez-Cordón, Josep M. Llibre, Marta Calvo, Felix Gutierrez, Daniel Podzamczer, Montserrat Laguno, et al. "Impact of prior virologic failure and nucleos(t)ide genotypic resistance mutations on the efficacy of switching from ritonavir-boosted protease inhibitors to raltegravir." Antiviral Therapy 20, no. 5 (2014): 487–92. http://dx.doi.org/10.3851/imp2812.

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Crespo, M., J. Navarro, M. Martinez-Rebollar, D. Podzamczer, P. Domingo, J. Mallolas, M. Saumoy, et al. "Improvement of BMD after Switching from Lopinavir/R Plus Two Nucleos(T)ide Reverse Transcriptase Inhibitors to Lopinavir/R Plus Lamivudine: OLE-LIP Substudy." HIV Clinical Trials 17, no. 3 (March 16, 2016): 89–95. http://dx.doi.org/10.1080/15284336.2016.1149929.

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Leeansyah, Edwin, Paul U. Cameron, Ajantha Solomon, Surekha Tennakoon, Pushparaj Velayudham, Maelenn Gouillou, Tim Spelman, et al. "Inhibition of Telomerase Activity by Human Immunodeficiency Virus (HIV) Nucleos(t)ide Reverse Transcriptase Inhibitors: A Potential Factor Contributing to HIV-Associated Accelerated Aging." Journal of Infectious Diseases 207, no. 7 (January 9, 2013): 1157–65. http://dx.doi.org/10.1093/infdis/jit006.

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Abram, Michael E., Manuel Tsiang, Kirsten L. White, Christian Callebaut, and Michael D. Miller. "A Cell-Based Strategy To Assess Intrinsic Inhibition Efficiencies of HIV-1 Reverse Transcriptase Inhibitors." Antimicrobial Agents and Chemotherapy 59, no. 2 (November 17, 2014): 838–48. http://dx.doi.org/10.1128/aac.04163-14.

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ABSTRACTDuring HIV-1 reverse transcription, there are increasing opportunities for nucleos(t)ide (NRTI) or nonnucleoside (NNRTI) reverse transcriptase (RT) inhibitors to stop elongation of the nascent viral DNA (vDNA). In addition, RT inhibitors appear to influence the kinetics of vDNA synthesis differently. While cell-free kinetic inhibition constants have provided detailed mechanistic insight, these assays are dependent on experimental conditions that may not mimic the cellular milieu. Here we describe a novel cell-based strategy to provide a measure of the intrinsic inhibition efficiencies of clinically relevant RT inhibitors on a per-stop-site basis. To better compare inhibition efficiencies among HIV-1 RT inhibitors that can stop reverse transcription at any number of different stop sites, their basic probability,p, of getting stopped at any potential stop site was determined. A relationship between qPCR-derived 50% effective inhibitory concentrations (EC50s) and this basic probability enabled determination ofpby successive approximation. On a per-stop-site basis, tenofovir (TFV) exhibited 1.4-fold-greater inhibition efficiency than emtricitabine (FTC), and as a class, both NRTIs exhibited an 8- to 11-fold greater efficiency than efavirenz (EFV). However, as more potential stops sites were considered, the probability of reverse transcription failing to reach the end of the template approached equivalence between both classes of RT inhibitors. Overall, this novel strategy provides a quantitative measure of the intrinsic inhibition efficiencies of RT inhibitors in the natural cellular milieu and thus may further understanding of drug efficacy. This approach also has applicability for understanding the impact of viral polymerase-based inhibitors (alone or in combination) in other virus systems.

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Shaw, T., T. Sozzi, and S. A. Locarnini. "699 COMBINATION THERAPY WITH NUCLEOS(T)IDE ANALOG REVERSE TRANSCRIPTASE INHIBITORS (NRTI): USING IN VITRO PHENOTYPING TO OPTIMISE NRTI COMBINATIONS FOR TREATMENT OF MULTIDRUG-RESISTANT HBV." Journal of Hepatology 48 (January 2008): S260—S261. http://dx.doi.org/10.1016/s0168-8278(08)60701-1.

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Jones, Scott A., Eisuke Murakami, William Delaney, Phillip Furman, and Jianming Hu. "Noncompetitive Inhibition of Hepatitis B Virus Reverse Transcriptase Protein Priming and DNA Synthesis by the Nucleoside Analog Clevudine." Antimicrobial Agents and Chemotherapy 57, no. 9 (June 17, 2013): 4181–89. http://dx.doi.org/10.1128/aac.00599-13.

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ABSTRACTAll currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit the DNA synthesis activity of the HBV polymerase. The polymerase is a unique reverse transcriptase (RT) that has a novel protein priming activity in which HP initiates viral DNA synthesis using itself as a protein primer. We have determined the ability of NRTI-triphosphates (TP) to inhibit HBV protein priming and their mechanisms of action. While entecavir-TP (a dGTP analog) inhibited protein priming initiated specifically with dGTP, clevudine-TP (a TTP analog) was able to inhibit protein priming independently of the deoxynucleoside triphosphate (dNTP) substrate and without being incorporated into DNA. We next investigated the effect of NRTIs on the second stage of protein priming, wherein two dAMP nucleotides are added to the initial deoxyguanosine nucleotide. The obtained results indicated that clevudine-TP as well as tenofovir DF-DP strongly inhibited the second stage of protein priming. Tenofovir DF-DP was incorporated into the viral DNA primer, whereas clevudine-TP inhibited the second stage of priming without being incorporated. Finally, kinetic analyses using the HBV endogenous polymerase assay revealed that clevudine-TP inhibited DNA chain elongation by HP in a noncompetitive manner. Thus, clevudine-TP appears to have the unique ability to inhibit HBV RT via binding to and distorting the HP active site, sharing properties with both NRTIs and nonnucleoside RT inhibitors.

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Stephan, Christoph, Brenda Dauer, Pavel Khaykin, Martin Stuermer, Peter Gute, Stephan Klauke, and Schlomo Staszewski. "Quadruple Nucleos(t)ide Reverse Transcriptase Inhibitors-Only Regimen of Tenofovir Plus Zidovudine/Lamivudine/Abacavir in Heavily Pre-Treated HIV-1 Infected Patients: Salvage Therapy or Backbone Only?" Current HIV Research 7, no. 3 (May 1, 2009): 320–26. http://dx.doi.org/10.2174/157016209788348010.

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López-Cortés, Luis F., Pompeyo Viciana, Rosa Ruiz-Valderas, Juan Pasquau, Josefa Ruiz, Fernando Lozano, Dolores Merino, et al. "Efficacy, safety and pharmacokinetic of once-daily boosted saquinavir (1500/100 mg) together with 2 nucleos(t)ide reverse transcriptase inhibitors in real life: a multicentre prospective study." AIDS Research and Therapy 7, no. 1 (2010): 5. http://dx.doi.org/10.1186/1742-6405-7-5.

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Balzarini, Jan, Kalyan Das, Jean A. Bernatchez, Sergio E. Martinez, Marianne Ngure, Sarah Keane, Alan Ford, et al. "Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics." Proceedings of the National Academy of Sciences 112, no. 11 (March 2, 2015): 3475–80. http://dx.doi.org/10.1073/pnas.1420233112.

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Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg2+ cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg2+, mimicking the chelation by the β- and γ-phosphate oxygens of dNTPs. α-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate-binding site, (iii) chelate one of the two active site Mg2+ ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg2+-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential.

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Rajotte, D., S. Tremblay, A. Pelletier, P. Salois, L. Bourgon, R. Coulombe, S. Mason, L. Lamorte, C. F. Sturino, and R. Bethell. "Identification and Characterization of a Novel HIV-1 Nucleotide-Competing Reverse Transcriptase Inhibitor Series." Antimicrobial Agents and Chemotherapy 57, no. 6 (April 1, 2013): 2712–18. http://dx.doi.org/10.1128/aac.00113-13.

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ABSTRACTSeveral groups have recently reported on the identification of nucleotide-competing reverse transcriptase inhibitors (NcRTIs), a new class of RT inhibitors. NcRTIs reversibly inhibit binding of the incoming nucleotide to the RT active site but do not act as chain terminators, unlike the nucleos(t)ide reverse transcriptase inhibitor (NRTI) class. We identified a novel benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI chemical series. Structure-activity relationship evaluation of this series with both RT and viral replication assays led to the identification of compound A, a new NcRTI. Compound A inhibited HIV-1 RT in a primer extension assay (50% inhibitory concentration, 2.6 nM) but had no measurable activity against human DNA polymerase γ at 10 μM. It potently inhibited HIV-1 replicationin vitro(50% effective concentration, 1.5 nM). The antiviral potency of compound A was unaffected by the presence of nonnucleotide RT inhibitor (NNRTI) mutations tested (L100I, K103N/Y181C, V106A, or Y188L). Notably, viruses encoding K65R were hypersusceptible to inhibition by compound A. Compound A also retained full activity against viruses encoding M184V.In vitroselection for resistant virus to compound A led to the selection of a single substitution within RT: W153L. A recombinant virus encoding the RT W153L was highly resistant to compound A (fold change, 160). W153 is a highly conserved residue in HIV RT and has not been previously associated with drug resistance. In summary, a novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered. These results further establish NcRTIs as an emerging class of antiretroviral agents.

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Gunsar, Fulya. "Delta Hepatitis." Reviews in Health Care 3, no. 4 (October 12, 2012): 229. http://dx.doi.org/10.7175/rhc.26734229-241.

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Hepatitis delta virus (HDV) is a defective RNA virus that requires HBsAg for replication and transmission. It can cause acute or chronic hepatitis. Chronic infection with HDV is one of the most severe and difficult to treat forms of viral hepatitis. It has been estimated that there is a total of 15-20 million HDV carriers in the world. This review focuses on two fundamental aspects of HDV infection. On the one hand, epidemiological data are summarized, which are essential to understand the real burden of this disease. After the HBV vaccination programs in many countries all over the world, HDV infection has decreased since 1980’s but this decline has not continued further in the last decade. Therefore, HDV infection is still an important public health problem in the world. On the other hand, therapeutic options are described. Currently, interferons are the only option for the treatment of chronic hepatitis delta infection, and pegylated-interferons have shown better results than conventional interferons (IFNs). Monotherapy of nucleos(t)ide analogs have been found ineffective against the HDV infection, but adefovir and pegylated-IFN combination therapy have had some advantages for reduction of HBsAg levels. Trials with more potent nucleoside analogs and pegylated-IFN could be effective in the treatment of chronic HDV infection. New agents like prenylation inhibitors, that can affect the interactions between the large HDV antigen and HBsAg in the HDV virion, will be a hope in treatment of HDV infection.

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Gunsar, Fulya. "Delta Hepatitis." Reviews in Health Care 3, no. 4 (October 12, 2012): 229–41. http://dx.doi.org/10.7175/rhc.v3i4.267.

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Hepatitis delta virus (HDV) is a defective RNA virus that requires HBsAg for replication and transmission. It can cause acute or chronic hepatitis. Chronic infection with HDV is one of the most severe and difficult to treat forms of viral hepatitis. It has been estimated that there is a total of 15-20 million HDV carriers in the world. This review focuses on two fundamental aspects of HDV infection. On the one hand, epidemiological data are summarized, which are essential to understand the real burden of this disease. After the HBV vaccination programs in many countries all over the world, HDV infection has decreased since 1980’s but this decline has not continued further in the last decade. Therefore, HDV infection is still an important public health problem in the world. On the other hand, therapeutic options are described. Currently, interferons are the only option for the treatment of chronic hepatitis delta infection, and pegylated-interferons have shown better results than conventional interferons (IFNs). Monotherapy of nucleos(t)ide analogs have been found ineffective against the HDV infection, but adefovir and pegylated-IFN combination therapy have had some advantages for reduction of HBsAg levels. Trials with more potent nucleoside analogs and pegylated-IFN could be effective in the treatment of chronic HDV infection. New agents like prenylation inhibitors, that can affect the interactions between the large HDV antigen and HBsAg in the HDV virion, will be a hope in treatment of HDV infection.

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Spertilli Raffaelli, C., B. Rossetti, L. Paglicci, M. Colafigli, G. Punzi, V. Borghi, M. Pecorari, et al. "Impact of transmitted HIV-1 drug resistance on the efficacy of first-line antiretroviral therapy with two nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor or a protease inhibitor." Journal of Antimicrobial Chemotherapy 73, no. 9 (June 25, 2018): 2480–84. http://dx.doi.org/10.1093/jac/dky211.

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Gianotti, Nicola, Patrizia Lorenzini, Alessandro Cozzi-Lepri, Andrea De Luca, Giordano Madeddu, Laura Sighinolfi, Carmela Pinnetti, et al. "Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL." Journal of Antimicrobial Chemotherapy 74, no. 9 (June 7, 2019): 2732–41. http://dx.doi.org/10.1093/jac/dkz237.

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Abstract Objectives Our aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL. Methods This was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ <200 cells/mm3 and HIV-RNA >5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone. Results A total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29–2.03) versus starting with NNRTIs; P < 0.001] and starting ART with InSTIs [aIRR (95% CI) 0.68 (0.48–0.96) versus starting with NNRTIs; P = 0.03] were independently associated with TF. Conclusions In patients starting ART with <200 CD4+ cells/mm3 and >5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

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Huang, Sung-Hsi, Shu-Wen Lin, Sui-Yuan Chang, Ya-Ting Lin, Hsin-Yun Sun, Wen-Chun Liu, Yi-Ching Su, Chien-Ching Hung, and Shan-Chwen Chang. "Effectiveness of half-a-tablet efavirenz plus 2 nucleos(t)ide reverse-transcriptase inhibitors as maintenance therapy with the guidance of therapeutic drug monitoring among virologically suppressed HIV-positive patients: A prospective study." Journal of Microbiology, Immunology and Infection 53, no. 1 (February 2020): 60–68. http://dx.doi.org/10.1016/j.jmii.2018.05.001.

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Curanovic, Dusica, Sharon K. Martens, Milka A. Rodriguez, Hunter A. Hammill, Christos J. Petropoulos, and Charles M. Walworth. "959. HIV-1 DNA Testing Identifies Drug Resistance in Viremic Patients with Pan-Sensitive Plasma Virus." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S510—S511. http://dx.doi.org/10.1093/ofid/ofaa439.1145.

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Abstract Background HIV-1 drug resistance mutations (DRMs) are lost from plasma virus in the absence of selective drug pressure. Therefore, viremic patients who present with pan-sensitive plasma HIV-1 may harbor archived drug resistance that hinders virologic suppression upon reinstatement of therapy. We sought to determine if testing HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) can identify drug resistance in patients with pan-sensitive plasma virus. Methods Sixty-four patients were identified who had HIV-1 RNA and HIV-1 DNA drug resistance testing performed on the same day and demonstrated pan-sensitive virus on the HIV-1 RNA test. Antiretroviral (ARV) resistance and DRMs identified by each test were compared between 66 test pairs. Patients were stratified by viral load (VL) to assess its impact on resistance detection using t-test and correlation analyses. Results The mean patient age was 37; 92% were female. Most (94%) were infected with HIV-1 subtype B, with an average VL of 110,000 c/mL (150 - 1,470,000 c/mL) at the time of resistance testing. Resistance to at least one ARV was reported on 20% (13/66) of HIV-1 DNA tests, and was associated with nucleos(t)ide and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), protease inhibitors (PIs), and integrase inhibitors (INIs) on 4.5%, 9%, 4.5%, and 6% of HIV-1 DNA reports, respectively. Across all HIV-1 DNA tests, 74 DRMs were identified that were not found in the plasma virus, including 12 NRTI, 16 NNRTI, 39 PI, and 7 INI DRMs; M184V was identified on 4.5% (3/66) of HIV-1 DNA reports. The mean VL was not significantly different between HIV-1 DNA tests reporting resistance to at least one ARV (101,000 c/mL) and those reporting pan-sensitivity (110,000 c/mL). Viral load at time of testing did not correlate with the number of ARVs to which resistance was reported. Conclusion In viremic patients with pan-sensitive plasma virus, HIV-1 DNA testing can identify drug resistance regardless of VL level. Assessment of drug resistance in HIV-1 DNA may be useful in designing suppressive ARV regimens for patients whose plasma virus DRMs fail to be identified due to lack of adherence or continuity of care. Disclosures Dusica Curanovic, PhD, Monogram Biosciences (Employee) Sharon K. Martens, MN, Monogram Biosciences (Employee) Milka A. Rodriguez, PhD, Monogram Biosciences (Employee) Christos J. Petropoulos, PhD, Monogram Biosciences (Employee) Charles M. Walworth, MD, Monogram Biosciences (Employee)

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Di Giambenedetto, S., M. Fabbiani, M. Colafigli, N. Ciccarelli, S. Farina, L. Sidella, A. D'Avino, et al. "Safety and feasibility of treatment simplification to atazanavir/ritonavir + lamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitors + atazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study)." Journal of Antimicrobial Chemotherapy 68, no. 6 (January 30, 2013): 1364–72. http://dx.doi.org/10.1093/jac/dkt007.

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Bailly, François, Pierre Pradat, Victor Virlogeux, and Fabien Zoulim. "Antiviral Therapy in Patients with Hepatitis C Virus-Induced Cirrhosis." Digestive Diseases 33, no. 4 (2015): 613–23. http://dx.doi.org/10.1159/000375359.

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Background: Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-α monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-α and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials. Conclusions: As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).

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Lam, Angela M., Suping Ren, Christine Espiritu, Mollie Kelly, Vincent Lau, Lingjie Zheng, George D. Hartman, Osvaldo A. Flores, and Klaus Klumpp. "Hepatitis B Virus Capsid Assembly Modulators, but Not Nucleoside Analogs, Inhibit the Production of Extracellular Pregenomic RNA and Spliced RNA Variants." Antimicrobial Agents and Chemotherapy 61, no. 8 (May 30, 2017). http://dx.doi.org/10.1128/aac.00680-17.

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ABSTRACT The hepatitis B virus (HBV) core protein serves multiple essential functions in the viral life cycle, and antiviral agents that target the core protein are being developed. Capsid assembly modulators (CAMs) are compounds that target core and misdirect capsid assembly, resulting in the suppression of HBV replication and virion production. Besides HBV DNA, circulating HBV RNA has been detected in patient serum and can be associated with the treatment response. Here we studied the effect of HBV CAMs on the production of extracellular HBV RNA using infected HepaRG cells and primary human hepatocytes. Representative compounds from the sulfonamide carboxamide and heteroaryldihydropyrimidine series of CAMs were evaluated and compared to nucleos(t)ide analogs as inhibitors of the viral polymerase. The results showed that CAMs blocked extracellular HBV RNA with efficiencies similar to those with which they blocked pregenomic RNA (pgRNA) encapsidation, HBV DNA replication, and Dane particle production. Nucleos(t)ide analogs inhibited viral replication and virion production but not encapsidation or production of extracellular HBV RNA. Profiling of HBV RNA from both culture supernatants and patient serum showed that extracellular viral RNA consisted of pgRNA and spliced pgRNA variants with an internal deletion(s) but still retained the sequences at both the 5′ and 3′ ends. Similar variants were detected in the supernatants of infected cells with and without nucleos(t)ide analog treatment. Overall, our data demonstrate that HBV CAMs represent direct antiviral agents with a profile differentiated from that of nucleos(t)ide analogs, including the inhibition of extracellular pgRNA and spliced pgRNA.

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Lam, Angela M., Christine Espiritu, Robert Vogel, Suping Ren, Vincent Lau, Mollie Kelly, Scott D. Kuduk, George D. Hartman, Osvaldo A. Flores, and Klaus Klumpp. "Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator against Hepatitis B Virus." Antimicrobial Agents and Chemotherapy 63, no. 1 (October 29, 2018). http://dx.doi.org/10.1128/aac.01734-18.

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ABSTRACT NVR 3-778 is the first capsid assembly modulator (CAM) that has demonstrated antiviral activity in hepatitis B virus (HBV)-infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA-containing virus particles with a mean antiviral 50% effective concentration (EC50) of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and a lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pregenomic RNA encapsidation, viral replication, and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 and 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achieved in mice and, thus, enabling efficacy studies in vivo. The overall preclinical profile of NVR 3-778 predicts antiviral activity in vivo and supports its further evaluation for safety, pharmacokinetics, and antiviral activity in HBV-infected patients.

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Mani, Nagraj, Andrew G. Cole, Janet R. Phelps, Andrzej Ardzinski, Kyle D. Cobarrubias, Andrea Cuconati, Bruce D. Dorsey, et al. "Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation." Antimicrobial Agents and Chemotherapy 62, no. 6 (March 19, 2018). http://dx.doi.org/10.1128/aac.00082-18.

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ABSTRACTAB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 μM; EC90= 0.33 to 1.32 μM) with no significant cytotoxicity (50% cytotoxic concentration > 10 μM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variantsin vitro. Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In ade novoinfection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein.In vitrodual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of thein vitrocombination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.

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Fischer, Matthew. "Comparison of Renal Function Between Tenofovir Disoproxil Fumarate and Other Nucleos(t)ide Reverse Transcriptase Inhibitors in Patients With Hepatitis B Virus Infection." Federal Practitioner, no. 38 (8) (August 1, 2021). http://dx.doi.org/10.12788/fp.0169.

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Chauhan, Ranjit, Qilan Li, Molly E. Woodson, Makafui Gasonoo, Marvin J. Meyers, and John E. Tavis. "Efficient Inhibition of Hepatitis B Virus Replication and cccDNA Formation by HBV Ribonuclease H Inhibitors During Infection." Antimicrobial Agents and Chemotherapy, September 13, 2021. http://dx.doi.org/10.1128/aac.01460-21.

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The Hepatitis B Virus (HBV) ribonuclease H (RNase H) is an attractive but unexploited drug target. Here, we addressed three limitations to the current state of RNase H inhibitor development: i) Efficacy has been assessed only in transfected cell lines; ii) Cytotoxicity data are from transformed cell lines rather than primary cells; and iii) It is unknown how the compounds work against nucleos(t)ide analog resistant HBV strains. Three RNase H inhibitors from different chemotypes, 110 (α-hydroxytropolone), 1133 (N-hydroxypyridinedione), and 1073 (N-hydroxynapthyridinone), were tested in HBV-infected HepG2-NTCP cells for inhibition of cccDNA accumulation and HBV product formation. 50% effective concentrations (EC 50 s) were 0.049-0.078 μM in the infection studies compared to 0.29-1.6 μM in transfected cells. All compounds suppressed cccDNA formation by >98% at 5 μM when added shortly after infection. HBV RNA, intracellular and extracellular DNA, and HBsAg secretion were all robustly suppressed. The greater efficacy of the inhibitors when added shortly after infection is presumably due to blocking amplification of the HBV cccDNA, which suppresses events downstream of cccDNA formation. The compounds had 50% cytotoxic concentrations (CC 50 s) of 16-100 μM in HepG2-derived cell lines but were non-toxic in primary human hepatocytes, possibly due to the quiescent state of the hepatocytes. The compounds had similar EC 50 s against replication of wild-type, Lamivudine-resistant and Adefovir/Lamivudine-resistant HBV, as expected because the RNase H inhibitors do not target the viral reverse transcriptase active site. These studies expand confidence in inhibiting the HBV RNase H as a drug strategy and support inclusion of RNase H inhibitors in novel curative drug combinations for HBV.

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Wu, Yibo, He Huang, and Yi Luo. "Management of Hepatitis B Virus in Allogeneic Hematopoietic Stem Cell Transplantation." Frontiers in Immunology 11 (February 4, 2021). http://dx.doi.org/10.3389/fimmu.2020.610500.

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The high morbidity of HBV reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is partially due to the intense immunologic potency of complex therapeutic regimens, the use of antithymocyte globulin and calcineurin inhibitors to prevent graft versus-host disease (GVHD), prolonged immune reconstitution, and hematological malignancies infected with hepatitis B virus (HBV). Immunosuppression results in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, the role of viral mutations during HBV reactivation needs to be validated. All individuals scheduled to receive allo-HSCT or wish to donate stem cells should be screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core (anti-HBc), and HBV-DNA. HBsAg-positive recipients of allo-HSCT have a high risk of HBV reactivation; thus, they should receive prophylactic antiviral therapy. The high barrier to resistance nucleos(t)-ide analogs (NAs) seems to be superior to the low barrier agents. Resolved-HBV recipients have a lower risk of HBV reactivation than HBsAg-positive recipients. Although prophylactic antiviral therapy remains controversial, regular monitoring of alanine transaminase (ALT) and HBV-DNA combined with preemptive antiviral treatment may be an optimized strategy. However, optimal antiviral therapy duration and time intervals for monitoring remain to be established. Accepting stem cells from HBsAg-positive donors is associated with a risk of developing HBV-related hepatitis. The overall intervention strategy, including donors and recipients, may decrease the risk of HBV-related hepatitis following HSCT from HBsAg positive stem cells. In this review, we summarize the issues of HBV in allo-HSCT, including HBV reactivation mechanism, HBsAg-positive recipients, HBV-resolved infection recipients, and donor-related factors, and discuss their significance.

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Collins, Sean E., Philip M. Grant, Francois Uwinkindi, Annie Talbot, Eric Seruyange, Deborah Slamowitz, Adeline Mugeni, et al. "A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans." Open Forum Infectious Diseases 3, no. 3 (2016). http://dx.doi.org/10.1093/ofid/ofw141.

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Abstract Background. Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods. We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results. Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, −7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions. A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

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Lambert-Niclot, Sidonie, Anders Boyd, Djeneba Fofana, Nadia Valin, Marc Wirden, Jean-Luc Meynard, Romain Palich, et al. "INSTI-Based Triple Regimens in Treatment-Naïve HIV-Infected Patients Are Associated With HIV-RNA Viral Load Suppression at Ultralow Levels." Open Forum Infectious Diseases 6, no. 5 (April 10, 2019). http://dx.doi.org/10.1093/ofid/ofz177.

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Abstract Background During antiretroviral therapy (ART), HIV-1-infected patients may present with ultralow (UL) HIV-RNA viral loads (VLs) below quantification levels of current assays. Reasons for UL-VL detection and its relation to virological rebound (VR) are unclear. Methods HIV-1-infected, ART-naïve patients followed at 2 university hospitals were included. All participants had an HIV-RNA >200 copies/mL at ART initiation and achieved a VL <50 copies/mL during ART. UL-VL was determined by the presence/absence of polymerase chain reaction signal detected using a commercially available assay (COBAS, TaqMan, Roche). Random-effects Poisson regression was used for assessing determinants of UL-VL not detected overtime and conditional risk set analysis for VR (1 VL > 200 copies/mL or 2 VL > 50 copies/mL) while accounting for frequency of VL measurements. Results Between 2009 and 2013, 717 patients initiated ART containing 2 nucleos(-t)ide reverse transcriptase inhibitors (NRTIs) plus a non-NRTI (29.4%), a protease inhibitor (58.4%), or an integrase-strand transfer inhibitor (INSTI; 12.1%). During a median (interquartile range) 3.4 (2.3–4.6) years, 676 (94.3%) patients achieved UL-VL not detected. In multivariable analysis, UL-VL not detected overtime was associated with younger age (P < .001), female gender (P = .04), lower baseline VL (P < .001), baseline CD4+ >500 vs <350/mm3 (P < .001), and INSTI-containing ART (P = .009). One hundred thirty-one (18.3%) patients had VR during follow-up, which was independently associated with a CD4/CD8 ratio <0.8 during follow-up (P = .01) and time spent with UL-VL not detected (P < .001). When UL-VL not detected occurred for ≥50% of the follow-up duration (n = 290), faster time to reach UL-VL not detected (P < .001), faster CD4+ T-cell count increase (P = .03), and faster CD4/CD8 ratio increase (P = .001) were observed. Conclusions VL suppression at an ultralow level is associated with INSTI-class ART initiation. Extensive VL suppression below ultralow detection could improve immune reconstitution.

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Journal articles on the topic 'Nucleos(t)ide inhibitors (NI)'

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