Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy.

Direct-acting antiviral (DAA) therapy, recently approved for patients with decompensated cirrhosis (DC) secondary to hepatitis C virus (HCV), is associated with improved hepatic function. We analyzed trends in liver transplant (LT) wait-listing (WL) to explore potential impact of effective medical therapy on WL registration. This is a cohort study using the Scientific Registry of Transplant Recipients database from 2003 to 2015. A total of 47,591 adults wait-listed for LT from HCV, hepatitis B virus (HBV), and nonalcoholic steatohepatitis (NASH) were identified. LT indication was defined as DC if the Model for End-Stage Liver Disease (MELD) at WL was ≥15 or hepatocellular carcinoma (HCC). Era of listing was divided into interferon (IFN; 2003-2010), protease inhibitor (PI; 2011-2013), and direct-acting antiviral (DAA; 2014-2015). Annual standardized incidence rates of WL were analyzed using Poisson regression. Adjusted incidences of LT WL for DC in HCV patients decreased by 5% in the PI era (P = 0.004) and 32% in the DAA era (P < 0.001) compared to the IFN era. Listing for DC in HBV also decreased in the PI (-17%; P = 0.002) and DAA eras (-24%; P < 0.001). Conversely, WL for DC in NASH increased by 41% in the PI era (P < 0.001) and 81% in the DAA era (P < 0.001). WL for HCC in both the HCV and NASH populations increased in both the PI and DAA eras (P < 0.001 for all) whereas HCC WL in HBV remained stable (P > 0.05 for all). CONCLUSION: The rate of LT WL for HCV complicated by DC has decreased by over 30% in the era of DAA therapy. Further reductions in WL are anticipated with increased testing, linkage to care, and access to DAA therapy. (Hepatology 2017;65:804-812).

Effect and mechanism of beta-L-D4A on DNA polymerase alpha.

AIM: To investigate the safety of beta-L-D4A on DNA polymerase alpha. METHODS: Ion exchange chromatography was used to separate DNA polymerase alpha from crude extract of human Hela cells. Detailed kinetic parameters were determined for beta-L-D4A against DNA polymerase alpha. RESULTS: DNA polymerase alpha was purified with 4% yield and 31000 units/mg specific activity. The Michaelis constant (Km = 3.22 micromol/L), 50% inhibition concentration (IC50 = 178.49 micromol/L) and inhibition constant (Ki = 126 micromol/L) of beta-L-D4A were determined by kinetic analysis. CONCLUSION: beta-L-D4A is a more safe nucleoside for hepatitis B virus infection with a lower host toxicity.

The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy.

PBL from HIV-infected patients were engrafted into CB-17 SCID mice to develop a novel small animal model for the study of HIV pathogenesis and therapy. Engraftment was achieved in 84% of mice, with human Ig (hu-Ig) levels and total human mononuclear cell recovery by peritoneal wash similar to those in control hu-PBL-SCID mice engrafted with uninfected donor cells. The hu-Ig produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus could be detected in 98% of mice by polymerase chain reaction and/or viral coculture. Viremia was first detected by quantitative polymerase chain reaction on day 7 (approximately 10,000 copies of viral RNA/ml of plasma) and persisted through day 17. Quasispecies analysis of amplified, cloned, proviral DNA of the V3 region of the env gene showed that nucleotide sequences from hu-HIV/PBL-SCID mouse peritoneal wash cells on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Relative to human CD4+ T cell recovery by peritoneal wash in control hu-PBL-SCID mice (CD4 = 19 +/- 2%; n = 40), severe CD4+ lymphocyte depletion (CD4 = 5 +/- 0.5%; n = 59; p < 0.001) was observed in untreated hu-HIV/PBL-SCID mice 18 to 25 days after engraftment. Treatment with 2'-beta-fluoro-2',3'-dideoxyadenosine, a nucleoside analogue, significantly reduced CD4+ T cell depletion (CD4 = 13 +/- 1; n = 59; p < 0.001) and the frequency of virus isolation (70%; p = 0.015) in the hu-HIV/PBL-SCID model. Boosting hu-Ig levels in the mice by injection of purified donor Ig with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus isolation. The administration of a mAb to TNF had minimal effects. These studies demonstrate that PBL from HIV-infected donors can engraft SCID mice; that HIV can be detected in the spleen, peritoneal wash cells, and blood of these mice; that HIV infection within the model results in rapid CD4+ T cell depletion; and that anti-retroviral therapy is effective in improving CD4+ T cell recovery and reducing the frequency of virus isolation. The hu-HIV/PBL-SCID mouse model thus represents a potentially useful model in which to study HIV pathogenesis and therapy.

Farmacología de las drogas empleadas en el tratamiento del SIDA / Pharmacology of the drugs employee in the treatment of AIDS

En esta revisión (transcripción de la presentación realizada en el Simposio SIDA, Avellaneda 1990) se enumeran las drogas empleadas para: 1)tratar las complicaciones del SIDA (solo algunos ejemplos, incluyendo foscarnet y glanciclovir); 2)realizar la inmunoterapia del SIDA; y 3)inhibir la replicación del HIV (quimioterápicos anti-HIV). En la segunda clase se enfatiza la necesidad de actuar precozmente (por ej., con valores no muy bajos de CD4), y se analizan evidencias preliminares sobre isoprinosina, timopentina y ditiocarb. En la tercera se analiza en detalle el mecanismo de acción de los dideoxinucleósidos, ejemplificando con la zidovudina, sus efectos adversos, sus limitaciones, en particular para tratamiento precoz, y el desarrrollo de resistencia en el HIV tanto in vitro como in vivo. Se analiza, también, el efecto del interferón * sobre la replicación viral y se esbozan los tratamientos más experimentales en farmacología clínica como el CD4 recombinante soluble) e in vitro (como los oligonucleótidos antisense). Pese a disponer de drogas efectivas en cada una de las tres categorías enunciadas, ninguna hace más que retrasar el curso de la infección hacia la destrucción del sistema inmune y muerte del paciente

Farmacología de las drogas empleadas en el tratamiento del SIDA / Pharmacology of the drugs employee in the treatment of AIDS

En esta revisión (transcripción de la presentación realizada en el Simposio SIDA, Avellaneda 1990) se enumeran las drogas empleadas para: 1)tratar las complicaciones del SIDA (solo algunos ejemplos, incluyendo foscarnet y glanciclovir); 2)realizar la inmunoterapia del SIDA; y 3)inhibir la replicación del HIV (quimioterápicos anti-HIV). En la segunda clase se enfatiza la necesidad de actuar precozmente (por ej., con valores no muy bajos de CD4), y se analizan evidencias preliminares sobre isoprinosina, timopentina y ditiocarb. En la tercera se analiza en detalle el mecanismo de acción de los dideoxinucleósidos, ejemplificando con la zidovudina, sus efectos adversos, sus limitaciones, en particular para tratamiento precoz, y el desarrrollo de resistencia en el HIV tanto in vitro como in vivo. Se analiza, también, el efecto del interferón * sobre la replicación viral y se esbozan los tratamientos más experimentales en farmacología clínica como el CD4 recombinante soluble) e in vitro (como los oligonucleótidos antisense). Pese a disponer de drogas efectivas en cada una de las tres categorías enunciadas, ninguna hace más que retrasar el curso de la infección hacia la destrucción del sistema inmune y muerte del paciente

A comparison of three nucleoside analogs with anti-retroviral activity on immune and hematopoietic functions in mice: in vitro toxicity to precursor cells and microstromal environment.

A number of 2'3'-dideoxynucleosides have been reported to markedly inhibit the in vitro growth of HIV, the causative agent of acquired immunodeficiency syndrome (AIDS). Clinical trials have shown that the continued therapeutic use of these nucleoside derivatives can be associated with adverse side effects. Since these side effects include myelotoxicity, as occurs in many patients treated with zidovudine (AZT; 3'-azido'3-deoxythymidine), and AIDS patients already represent an immunologically compromised population, we examined the immunological effects of three nucleoside inhibitors, including zidovudine, 2'3'-dideoxycytidine, and 2'3'-dideoxyadenosine (DDA) in a mouse model. Additional studies were conducted to further determine and characterize the potential toxic effects associated with these drugs on the hematopoietic system. Of the three dideoxynucleosides examined, only DDA altered immune functions following a 30-day subchronic exposure in mice. This was evidenced by a marked suppression of the antibody plaque-forming cell response and a slight alteration in macrophage function. None of the nucleoside derivatives affected bone marrow function following in vivo exposure, although AZT produced a mild macrocytic anemia in vivo and was myelotoxic when added in vitro to bone marrow cell cultures. In vitro studies indicated that AZT was capable of affecting both proliferating stem cells as well as the stromal cell microenvironment, both of which play a role in hematopoiesis. These data indicate that, although the mice may not develop the identical toxicities associated with nucleoside therapy in humans, certain adverse immunological and hematological effects were readily discerned which could have relevance to humans.