gs-7340 and Fatigue

To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug.. A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study.. Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days.. Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF.. Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.

Topics: Adenine; Adult; Alanine; Anti-Retroviral Agents; Area Under Curve; Dose-Response Relationship, Drug; Fatigue; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nausea; Organophosphates; Organophosphonates; RNA, Viral; Single-Blind Method; Statistics, Nonparametric; Tenofovir; Viral Load; Young Adult

Antiretroviral post-exposure prophylaxis (PEP) is recommended to prevent HIV infection after a high-risk exposure, but current regimens have presented challenges in tolerability, regimen completion, and potential drug-drug interactions. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide [BIC/FTC/tenofovir alafenamide (TAF)] is effective for HIV treatment, it was evaluated for use for PEP.. Boston community health center.. Individuals accessing PEP were enrolled in an open-label study of coformulated BIC/FTC/TAF, taken as one pill daily for 28 days. Pearson's χ2 and Fisher's exact tests were used to assess whether BIC/FTC/TAF differed with respect to side effects and regimen completion rates compared with historical PEP regimens.. Between August, 2018 and March, 2020, 52 individuals enrolled in the study. Most identified as cisgender gay (67.3%) or bisexual (11.5%) men, but 7.7% identified as cisgender heterosexual men and 3.8% cisgender heterosexual women. The most common regimen side effects were nausea or vomiting (15.4%), fatigue (9.6%), and diarrhea/loose stools (7.7%), which were less common than historical controls using other PEP regimens, including those containing other integrase strand transfer inhibitors. Only 1 participant discontinued the regimen because of fatigue, and all other side effects were self-limited. Almost all participants (90.4%) completed the indicated regimen, which was a higher completion rate compared with earlier PEP regimens, and none became HIV-positive.. BIC/FTC/TAF coformulated as a single daily pill was found to be safe, well-tolerated, and highly acceptable when used for PEP, and compared more favorably than historical PEP regimens used at an urban health center.

Topics: Adenine; Alanine; Amides; Anti-HIV Agents; Emtricitabine; Fatigue; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Male; Piperazines; Post-Exposure Prophylaxis; Pyridones; Tenofovir