Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection.

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by the United States Food and Drug Administration (FDA) on August 30, 2018, for the treatment of HIV infection in adult patients. The product was also approved in the E.U. and Japan in November 2018 and January 2020, respectively. It is currently available as a single stand-alone tablet as well as part of a single-tablet regimen in a fixed-dose combination with tenofovir disoproxil and lamivudine. Similarly to other NNRTIs, doravirine exerts its antiviral effect through a noncompetitive inhibition of HIV-1 reverse transcriptase. It has a novel resistance pathway so that it retains in vitro activity against clinically relevant NNRTI viral mutations K103N, Y181C and G190A. In randomized clinical trials, doravirine was noninferior to efavirenz- and darunavir-based regimens, with fewer adverse events. Doravirine has a more favorable drug interaction profile compared with earlier NNRTIs as it neither inhibits nor induces the cytochrome P450 3A4 (CYP3A4) enzyme. Doravirine has been added to the category of Recommended Initial Regimens in Certain Clinical Situations in the United States Department of Health and Human Services Antiretroviral Guidelines for Adults and Adolescents.

Hepatitis C virus upregulates B-cell receptor signaling: a novel mechanism for HCV-associated B-cell lymphoproliferative disorders.

B-cell receptor (BCR) signaling is essential for the development of B cells and has a critical role in B-cell neoplasia. Increasing evidence indicates an association between chronic hepatitis C virus (HCV) infection and B-cell lymphoma, however, the mechanisms by which HCV causes B-cell lymphoproliferative disorder are still unclear. Herein, we demonstrate the expression of HCV viral proteins in B cells of HCV-infected patients and show that HCV upregulates BCR signaling in human primary B cells. HCV nonstructural protein NS3/4A interacts with CHK2 and downregulates its activity, modulating HuR posttranscriptional regulation of a network of target mRNAs associated with B-cell lymphoproliferative disorders. Interestingly, the BCR signaling pathway was found to have the largest number of transcripts with increased association with HuR and was upregulated by NS3/4A. Our study reveals a previously unidentified role of NS3/4A in regulation of host BCR signaling during HCV infection, contributing to a better understanding of the molecular mechanisms underlying HCV-associated B-cell lymphoproliferative disorders.

Sofosbuvir for the treatment of chronic hepatitis C virus infection.

Sofosbuvir is a nucleotide analogue selective inhibitor of the RNA-directed RNA polymerase (NS5B) enzyme of the hepatitis C virus (HCV) genome. It has shown potent antiviral activity across all HCV genotypes and in a variety of patient populations, including treatment-naive patients; treatment-experienced patients who had failed previous standard therapy; patients with decompensated liver disease, including cirrhosis; and HIV co-infected patients. It is administered as a single, once-daily 400-mg tablet, has no food restrictions, has low potential for drug interactions, and requires no dose adjustment in mild to moderate kidney or liver impairment. When sofosbuvir is combined with pegylated interferon and/or ribavirin, its clinical and laboratory safety profile is similar to that which is expected from pegylated interferon or ribavirin alone. Rates of treatment discontinuation and dose reduction with sofosbuvir-containing regimens were lower than those commonly observed with pegylated interferon and ribavirin.

Dolutegravir, an HIV integrase inhibitor for the treatment of HIV infection.

Dolutegravir, a next-generation integrase strand transfer inhibitor, was recently approved by the United States Food and Drug Administration to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those who have been treated with other integrase strand transfer inhibitors. Dolutegravir is the first stand-alone agent in its class, with a pharmacokinetic profile that allows once-daily administration without the requirement for pharmacologic boosting. It is metabolized primarily by UDP-glucuronosyltransferase 1-1 (UGT1A1) and is expected to have a limited propensity for drug-drug interactions. Furthermore, dolutegravir retains significant virologic activity against raltegravir- or elvitegravir-associated HIV-1 resistance mutations.

Predictors of early treatment discontinuation in a cohort of patients treated with boceprevir-based therapy for hepatitis C infection.

In this real-world cohort, 49% of patients stopped boceprevir-based hepatitis C therapy early, with only 20% stopping due to treatment futility. Having more comorbidities was significantly associated with early discontinuation. Tolerability of boceprevir-based regimens may be substantially worse than reported in clinical trials, particularly for patients with comorbidities.

Simeprevir: a macrocyclic HCV protease inhibitor.

Simeprevir is a macrocyclic NS3/4A HCV protease inhibitor with potent activity against genotypes 1, 2, 4, 5 and 6 of the hepatitis C virus (HCV). Phase II and III studies of simeprevir combined with pegylated interferon (peg-IFN) and ribavirin (RBV) demonstrated that the combination was safe and effective in HCV genotype 1 patients, with more than 75% of treatment-naive patients attaining a sustained virological response (SVR). Simeprevir is administered once daily as a single 150-mg capsule. It has a moderate drug interaction potential, but less than that of the first-generation HCV protease inhibitors. Based on positive results from the product's phase III clinical program, simeprevir was approved and launched in Japan, the U.S. and Canada in late 2013 for use in combination with peg-IFN/RBV in HCV genotype 1 infections. Phase II interferon-free studies of simeprevir are ongoing.

Current status of treatment for chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is responsible for substantial mortality and morbidity worldwide. Until recently, the standard of care for the treatment of chronic HCV infection had been a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). The recent availability of two directly acting agents, telaprevir and boceprevir, has led to significantly improved outcomes for those patients with HCV genotype 1. Unfortunately, each of these agents must be combined with peg-IFN and RBV for optimal efficacy, and substantial treatment-related toxicity continues to challenge clinicians. However, the drug development pipeline for chronic HCV infection is very robust and the emergence of new therapies and therapeutic strategies in the near future for managing chronic HCV infection is eagerly anticipated.

Telaprevir: looking for a sustained virologic response in hepatitis C virus infection.

Telaprevir, a hepatitis C virus (HCV) NS3/NS4A protease inhibitor, was recently approved by the U.S. Food and Drug Administration for the treatment of chronic HCV genotype 1 infection. When given in combination with pegylated interferon and ribavirin, it demonstrated improved efficacy over conventional pegylated interferon and ribavirin therapy. Improvement in efficacy was also noted in African American patients who traditionally respond less well to conventional anti-HCV treatment. While the role of telaprevir in the management of chronic HCV infection remains to be fully defined, its development and licensure represents an important milestone in anti-HCV therapeutics.

Boceprevir.

Boceprevir is a hepatitis C virus (HCV) serine protease NS3 inhibitor that has recently been approved by the U.S. Food and Drug Administration, the European Medicines Agency and Health Canada for the treatment of chronic genotype 1 HCV infection. It has potent in vitro antiviral activity against HCV genotypes 1a and 1b and is primarily metabolized via the aldoketoreductase pathway with minor cytochrome P450 3A4 metabolism. Boceprevir is well tolerated with few drug-drug interactions which are easy to manage; no dose adjustment is required in patients with hepatic or renal impairment. Phase I trials of boceprevir demonstrated favorable pharmacokinetic, metabolic and safety profiles. Phase II and III trials of boceprevir confirmed the antiviral activity of the drug and its use at a dose of 800 mg three times daily. Clinical trials in treatment-naive and previously treated HCV-infected patients demonstrated a 26% and 45% (respectively) improvement in sustained viral response when boceprevir was added to standard pegylated interferon and ribavirin anti-HCV therapy. Boceprevir is the first-in-class of an exciting new phase of HCV treatment.

Tuberculous peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: case report and review.

A case of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis (CAPD) in a 37-year-old man who presented with fever, abdominal pain, and a malfunctioning Tenckhoff catheter is reported. The patient was initially treated for presumed bacterial peritonitis but remained febrile and had persistent abdominal pain and peritoneal fluid pleocytosis, despite broad-spectrum antibiotic therapy. Mycobacterium tuberculosis was isolated in a culture of peritoneal fluid, and the patient responded promptly to antituberculous therapy. More than 50 cases of tuberculous peritonitis complicating CAPD that have been reported in the English-language literature since the initial case was reported in 1980 are reviewed. The most common symptoms are fever (78%), abdominal pain (92%), and cloudy dialysate (90%); 76% of cases had a predominance of polymorphonuclear cells in peritoneal fluid. A smear for acid-fast bacilli or a culture was positive in 73% of cases. The peritoneal dialysis catheter was removed in 53% of cases, although this was rarely considered necessary for cure of tuberculosis. The attributable mortality rate is 15%, with the most significant factor being treatment delay (mean time from presentation to initiation of treatment, 6.74 weeks). We conclude that tuberculosis is an important diagnostic consideration for CAPD patients with peritonitis that is refractory to broad-spectrum antibiotics.

Penicillin dosing for pneumococcal pneumonia.

Most textbook authors still endorse penicillin G as the specific antibiotic of choice for pneumococcal pneumonia. However, problems with early precise etiologic diagnosis of pneumonia and the emergence of drug-resistant pneumococci cause penicillin to be seldom used for this purpose today. A third explanation for the infrequent use of penicillin is lack of clear consensus dosing guidelines. Emergence of pneumococci resistant to the newer cephalosporins and concerns about overuse of vancomycin, however, have prompted renewed interest in the development of precise, rapid methods for diagnosis of pneumococcal pneumonia with the implication that penicillin might be used more frequently. We review several issues concerning penicillin dosing: intermittent vs continuous therapy, high dose vs low dose, relationship of dose to resistance, and cost-effective pharmacology. An optimum "high-dose" regimen for life-threatening pneumococcal pneumonia in a 70-kg adult consists of a 3 million unit (mu) loading dose followed by continuous infusion of 10 to 12 mu of freshly prepared drug every 12 h. The maintenance dose should be reduced in elderly patients and in patients with renal failure according to the following formula: dose (mu/24 h = 4+[creatinine clearance divided by 7]). This regimen provides a penicillin serum level of 16 to 20 microg/mL, which should suffice for all but the most highly resistant strains (minimum inhibitory concentration > or = 4 microg/mL). Newer cephalosporins and vancomycin can be reserved for patients with suspected meningitis or endocarditis or for localities in which highly resistant pneumococci are known to be prevalent.