The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials.

Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined.

Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease.

Lysyl oxidase like-2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks.

The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options.

Background & Aims: Although patients with cryptogenic cirrhosis have historically been considered as having "burnt-out" non-alcoholic steatohepatitis (NASH), some controversy remains. The aim of this study was to compare outcomes of patients with cryptogenic cirrhosis and NASH-related cirrhosis from a cohort with longitudinal follow-up data.

Methods: Patients with cryptogenic cirrhosis or NASH cirrhosis were screened for a clinical trial.

GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease.

Background & Aims: De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.

Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis.

Background & Aims: Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis.

Methods: We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks.

Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.

Background & Aims: Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH.

Unusual five amino acid insert within subtype C HIV-1 envelope contributes to dual-tropism (X4R5).

During the course of HIV infection, some HIV-1 viruses switch from using the CCR5 (R5) coreceptor to using CXCR4 (X4). Here, we describe two subtype C isolates from a Zimbabwean patient that switched from using R5 to using both R5 and X4 with an accompanying addition of five amino acids to the V3 loop region of envelope. The insert appears to be derived from the human genome rather than a duplication within HIV-1.

Envelope coreceptor tropism, drug resistance, and viral evolution among subtype C HIV-1-infected individuals receiving nonsuppressive antiretroviral therapy.

Background: In resource-constrained settings, antiretroviral treatment (ART) is often continued based on clinical and CD4 responses, without virologic monitoring. ART with incomplete viral suppression was assessed in 27 subjects with subtype C HIV-1.

Methods: Plasma HIV-1 RNA, drug resistance, viral tropism, and evolution in polymerase (pol) and envelope (env) genes were measured.