The median-effect equation derived from the mass-action law principle at equilibrium-steady state via mathematical induction and deduction for different reaction sequences and mechanisms and different types of inhibition has been shown to be the unified theory for the Michaelis-Menten equation, Hill equation, Henderson-Hasselbalch equation, and Scatchard equation. It is shown that dose and effect are interchangeable via defined parameters. This general equation for the single drug effect has been extended to the multiple drug effect equation for n drugs. These equations provide the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI 1 indicate synergism, additive effect, and antagonism, respectively. Based on these algorithms, computer software has been developed to allow automated simulation of synergism and antagonism at all dose or effect levels. It displays the dose-effect curve, median-effect plot, combination index plot, isobologram, dose-reduction index plot, and polygonogram for in vitro or in vivo studies. This theoretical development, experimental design, and computerized data analysis have facilitated dose-effect analysis for single drug evaluation or carcinogen and radiation risk assessment, as well as for drug or other entity combinations in a vast field of disciplines of biomedical sciences. In this review, selected examples of applications are given, and step-by-step examples of experimental designs and real data analysis are also illustrated. The merging of the mass-action law principle with mathematical induction-deduction has been proven to be a unique and effective scientific method for general theory development. The median-effect principle and its mass-action law based computer software are gaining increased applications in biomedical sciences, from how to effectively evaluate a single compound or entity to how to beneficially use multiple drugs or modalities in combination therapies.

http://www.protocol-online.org/forums/uploads/monthly_09_2010/post-8165-008503000%201284677034.ipb

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here we show that circulating microbial products, probably derived from the gastrointestinal tract, are a cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, which we used as an indicator of microbial translocation, was significantly increased in chronically HIV-infected individuals and in simian immunodeficiency virus (SIV)-infected rhesus macaques (P <or= 0.002). We show that increased lipopolysaccharide is bioactive in vivo and correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy seemed to reduce microbial translocation partially. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, microbial translocation did not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide new directions for therapeutic interventions that modify the consequences of acute HIV infection.

/pdf/microbial-translocation-is-a-cause-of-systemic-immune-x0b1juxgn5.pdf

Microbial translocation is a cause of systemic immune activation in chronic HIV infection

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.23190

Chronic hepatitis B: Update 2009

Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.

Receptor Binding and Membrane Fusion in Virus Entry: The Influenza Hemagglutinin

A method of treating HIV infection in a human patient wherein the infecting HIV strain has become resistant to atazanavir, the method comprising administration of a therapeutically effective amount of a combination of atazanavir or a pharmaceutically acceptable salt thereof, and at least one other HIV protease inhibitor. A method for enhancing the effectiveness of a second HIV protease inhibitor in treating HIV infection in a human patient whose HIV strain has become resistant to atazanavir or a pharmaceutically acceptable salt thereof, comprising administering to said human patient an amount of atazanavir or a pharmaceutically acceptable salt thereof effective in maintaining the resistant strain, in combination with the second HIV protease inhibitor. The resistance to atazanavir in the human is manifested by the existence of the signature mutation consisting of I50L mutation in the HIV protease.

A method of treating hiv infection in atazanavir resistant patients using a combination of atazanavir and another protease inhibitor

Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1′ Compounds: Correlation Between Lipophilicity and Cytotoxicity.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite‐duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI‐H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI‐H2158 (5–500 mg) or placebo; Part B, participants received multiple doses of ABI‐H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI‐H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety‐three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment‐emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI‐H2158; there were no deaths, SAEs or Grade 4 TEAEs. In Part A, median time to maximum ABI‐H2158 plasma concentration (Tmax) and mean terminal elimination half‐life (t½) were 1–4 and 9.8–20.7 h, and area under the plasma concentration‐time curve increased dose proportionally. In Part B, Day 10 Tmax was 2 h, mean t½ was 15.5–18.4 h, and exposure accumulated 1.7‐ to 3.1‐fold. In Part C, Day 14 Tmax was 1 h, exposure accumulated 1.4‐ to 1.8‐fold, and ABI‐H2158 was associated with >2 log10 declines in HBV nucleic acids. In conclusion, ABI‐H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing.

Richard J. Colonno

Papers

A method of treating hiv infection in atazanavir resistant patients using a combination of atazanavir and another protease inhibitor

Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1′ Compounds: Correlation Between Lipophilicity and Cytotoxicity.

Safety, pharmacokinetics and antiviral activity of ABI‐H2158, a hepatitis B virus core inhibitor: A randomized, placebo‐controlled phase 1 study

THU-216-Rapid turnover of HBV cccDNA in nucleoside-treated chronic hepatitis B patients during drug resistance emergence and breakthrough

P.087 High barrier to resistance results in no emergence of entecavir resistance in nucleoside-naive subjects during the first two years of therapy