Novel Adherence Interventions in Perinatally Acquired HIV: PEG Insertion and Pill Glide.

BACKGROUND AND OBJECTIVES: Children, adolescents and young adults (CAYA) with perinatally acquired human immunodeficiency virus (PaHIV) need lifelong antiretroviral therapy (ART) to suppress viral load (VL), maintain health and prevent onward transmission. Many struggle with adherence despite multidisciplinary input. We assessed ART adherence outcomes following two novel interventions: percutaneous endoscopic gastrostomy (PEG) and Pill Glide®, a fruit-flavoured lubricant spray aiding tablet swallowing. METHODS: Retrospective cohort analysis by database and case-note review of PaHIV CAYA aged < 25 years receiving PEG or Pill Glide® between 1995 and 2017 at a single tertiary centre. RESULTS: Nineteen PEGs were inserted in 15 CAYA at a median age of 17 (IQR 6-22) years, median CD4 count 40 cells/µL (IQR 10-220). A viral load (VL) < 50 copies/mL was achieved in 93% with PEG ART. At last follow-up all were alive, median age 23 years (IQR 22-28). Nine had PEG removed, after a median of 3.3 years (range 0.5-6.8), with a current VL < 50 copies/mL, median CD4 count 940 cells/µL (IQR 261-1353) sustained post PEG removal median was 5.4 years (range 1.5-17.8) previously. From 2017 seven CAYA received Pill Glide®, median age 10 years (IQR 7-14), median CD4 count 898 cells/µL (range 148-1943), 6/7 with a suppressed VL. All reported increased ease in tablet swallowing and transitioned successfully from crushed tablets/liquids to tablets. At follow-up, all patients had a suppressed VL. CONCLUSIONS: Whilst PEG insertion markedly improved rates of viral suppression in CAYA struggling with ART adherence, the use of novel less invasive aids such as Pill Glide® requires further exploration.

A Phase I study to assess the safety, tolerability and pharmacokinetic profile of boceprevir and sildenafil when dosed separately and together, in healthy male volunteers.

OBJECTIVES: Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers. METHODS: Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs). RESULTS: All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2. CONCLUSIONS: Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested.

Rilpivirine exposure in plasma and sanctuary site compartments after switching from nevirapine-containing combined antiretroviral therapy.

OBJECTIVES: Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine. METHODS: HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively). RESULTS: Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8-37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7-1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3-7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90. CONCLUSIONS: Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP.

Are disulfiram-like reactions associated with abacavir-containing antiretroviral regimens in clinical practice?

Abacavir is metabolized primarily by two enzymes: alcohol dehydrogenase and gluconyl transferase. Under normal conditions, alcohol is hepatically cleared via alcohol dehydrogenase to acetaldehyde, and subsequently by acetaldehyde dehydrogenase (ACD) to acetic acid. Disulfiram acts as an ACD blocker. Abacavir may also act as an inhibitor of alcohol dehydrogenase, which raises the possibility of disulfiram-like reactions (if complete inhibition occurs) or reduced alcohol tolerance (if partial inhibition occurs) occurring with abacavir therapy.