gs-7340 and adefovir

A woman in her 60s visited our hospital due to elevation of ALP (1357U/L). The patient had been treated with lamivudine (LAM) in 2005, LAM+adefovir (ADV) in 2009, and ADV+entecavir in 2015 for chronic hepatitis B (CH-B). The ALP isozyme was predominantly bone type. Urinary β-2 microglobulin (MG) and α-1MG increased to 49635μg/L and 64.1mg/L, respectively. Though no fractures were found during bone scintigraphy, the patient was diagnosed with Fanconi syndrome. However, 3 months after switching from ADV to tenofovir alafenamide (TAF), ALP decreased to 856U/L, and urinary β-2MG and α-1MG decreased to 624μg/L and 6.0mg/L, respectively. Fanconi syndrome should be considered when an increase in ALP is observed in patients treated with ADV, and urinary β-2MG and α-1MG assays are useful for establishing a diagnosis. Switching from ADV to TAF was an effective therapeutic option.

Topics: Adenine; Alanine; Alkaline Phosphatase; Antiviral Agents; Biomarkers; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Fanconi Syndrome; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Middle Aged; Organophosphonates; Tenofovir; Tomography, X-Ray Computed; Treatment Outcome

Topics: Absorptiometry, Photon; Adenine; Alanine; Coinfection; Dose-Response Relationship, Drug; Fanconi Syndrome; Hepatitis B, Chronic; HIV Infections; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Organophosphonates; Tenofovir; Treatment Outcome

The synthesis and in vitro biological evaluation of novel phosphonamidate and phosphonodiamidate prodrugs of adefovir and tenofovir are reported. The selected synthetic approach from free phosphonic acid via bis-trimethylsilyl ester intermediates affords (L)-alanine ester derivatives in 10-70% yields. When assessed for their anti-HIV activity, all the prodrugs showed submicromolar activity. Noteworthy, the most potent derivative in the adefovir series contained a 5,6,7,8-tetrahydronaphtyl group, herein reported for the first time as an aryl moiety in a ProTide. A pronounced cytostatic activity of the above prodrugs is also reported. Selected compounds were tested for their antiproliferative activity against HPV-transformed cells and they were found significantly more active in comparison to their parent compounds. In this study a slightly improved activity of the adefovir derivatives over those of tenofovir was also noticed. However, no specificity for naturally HPV-transformed cell lines was observed.

Topics: Adenine; Antineoplastic Agents; Antiviral Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HeLa Cells; HIV; HIV Infections; Humans; Microbial Sensitivity Tests; Molecular Structure; Organophosphonates; Papillomavirus Infections; Prodrugs; Structure-Activity Relationship; Tenofovir; Tumor Cells, Cultured