Search

BackgroundThe pharmacokinetics of bictegravir (BIC) and its association with the decay of human immunodeficiency virus (HIV)–1 RNA in genital fluids and the rectum have not yet been addressed.MethodsWe conducted a prospective, multicenter study of antiretroviral-naive people living with HIV-1 and initiating BIC/emtricitabine (FTC)/tenofovir alafenamide (TAF). HIV-1 RNA was measured (limit of quantification, 40 copies/mL) in blood plasma (BP), seminal plasma (SP), rectal fluid (RF), and cervicovaginal fluid (CVF) at baseline; Days 3, 7, 14, and 28; and Weeks 12 and 24. Total and protein-unbound BIC concentrations at 24 hours postdose (C24h) were quantified in BP, SP, CVF and rectal tissue (RT) on Day 28 and Week 12 using a validated liquid chromatography-tandem mass spectrometry assay.ResultsThe study population comprised 15 males and 8 females. In SP, RF, and CVF, the baseline HIV-1 RNA was >40 copies/mL in 12/15, 13/15, and 4/8 individuals, respectively, with medians of 3.54 (2.41–3.79), 4.19 (2.98–4.70), and 2.56 (1.61–3.56) log10 copies/mL, respectively. The initial decay slope was significantly lower in SP than in RF and BP. The time to undetectable HIV-1 RNA was significantly shorter in SP and RF than in BP. All women achieved undetectable HIV-1 RNA in CVF at Day 14. The median total BIC concentrations in SP, RT, and CVF were 65.5 (20.1–923) ng/mL, 74.1 (6.0–478.5) ng/g, and 61.6 (14.4–1760.2) ng/mL, respectively, representing 2.7%, 2.6%, and 2.8% of the BP concentration, respectively, while the protein-unbound fractions were 51.1%, 44.6%, and 42.6%, respectively.ConclusionsBIC/FTC/TAF led to rapid decay of HIV-1 RNA in genital and rectal fluids. Protein-unbound BIC concentrations in SP, RT, and CVF highly exceeded the half-maximal effective concentration (EC50) value (1.1 ng/mL).Clinical Trials RegistrationEudraCT 2018-002310-12.

Background This study assessed the penetration and efficacy of tenofovir alafenamide (TAF) in the male genital tract (MGT) and the semen quality of individuals infected with human immunodeficiency virus (HIV)-1 who were treated with a TAF-containing regimen. Methods This was a prospective, open-label, single-arm study of 14 virologically-suppressed, HIV-1–infected men on stable antiretroviral therapy with elvitegravir, cobicistat, emtricitabine (E/C/F) and tenofovir disoproxil fumarate (TDF) who switched to E/C/F and TAF. At baseline (pre-switch) and at 12 weeks post-switch, we measured HIV-1 RNA in seminal plasma (SP) and blood plasma (BP), tenofovir (TFV) in SP and BP, and TFV-diphosphate (dp) in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells (SMCs) at the end of the dosing interval (C24h). Semen quality was assessed before switching and after 12 weeks on TAF. Results With TAF, TFV C24 was 11.9-fold higher in SP than in BP. This concentration was significantly lower than TFV C24 in SP with TDF, but 9.6-fold higher than the 50% inhibitory concentration (IC50) (11.5 ng/mL). By contrast, the median TFV-dp concentration achieved with TAF in SMCs was 6% that of TFV-dp in PBMCs. The TFV-dp SMC:PBMC ratio was also significantly lower with TAF. Nonetheless, TFV-dp C24 in SMC was comparable with TAF and TDF. All the patients had HIV-1 RNA Conclusions Extracellular and intracellular seminal TFV distribution differs between TAF and TDF. Nevertheless, both formulations, combined with elvitegravir/cobicistat/emtricitabine, maintained HIV-1 RNA suppression in semen. Differences in MGT distribution were not associated with differences in semen quality. Clinical Trials Registration EudraCT: 2016-001371-69

Despite the outstanding progress made with the advent of preventive antiviral strategies, cytomegalovirus (CMV) infection remains the most common opportunistic infection in kidney transplant recipients. Although primary Infection in immunocompetent hosts is usually asymptomatic, transplant recipients are at increased risk of developing CMV infection in the period immediately after transplantation. This poses a critical challenge to both graft and patient survival [1, 2]. The T-cell immune response to CMV is known to be of primary importance in controlling viral infection [3–5]. However, the humoral adaptive immune response, evaluated by serological CMV-specific immunoglobulin (Ig) G titers, is the only marker currently available for immune-risk stratification in clinical practice. Unfortunately, this surrogate approach does not entirely help identify all truly immune-sensitized transplant recipients at lower risk of CMV infection after transplantation. Indeed, there is clear clinical evidence for this position; although most CMV IgG–seropositive (sR+) transplant recipients receiving a seropositive allograft are unlikely to develop CMV infection after transplantation, up to 20%–30% may experience CMV disease without antiviral prophylaxis [6, 7]. Furthermore, even though most seronegative recipients of seropositive allografts will develop CMV infection if not treated with antiviral prophylaxis, a considerable proportion (30%–40%) will never experience CMV infection [8]. An important body of evidence suggests that monitoring CMV-specific T-cell responses, at different times before and after transplantation, may allow a more accurate characterization of the immune risk profile against CMV infection [9–13]. Measuring circulating CMV-specific IgG antibodies is the most common method of assessing the CMV-specific B-cell sensitization status. However, this approach may underestimate the true magnitude of the humoral immune response, because it excludes the whole memory B-cell pool. In fact, memory B cells can exist in the absence of detectable serum antibody levels [14, 15], but are able to rapidly differentiate into antibody-secreting cells (ASCs), which may be highly relevant for an effective humoral response. Therefore, a direct assessment of the CMV-specific memory T and B cells in transplant recipients could provide a more complete picture of their adaptive memory immune response against CMV. This study aimed to investigate the baseline CMV-specific memory T- and B-cell compartments using highly sensitive enzyme-linked immunospot (ELISPOT) assays in a cohort of seronegative and seropositive kidney transplant recipients. We measured the frequency of CMV-specific interferon (IFN) γ– and IgG–producing memory T and B cells and determined whether it could illustrate the immune sensitization status against CMV more accurately than circulating CMV IgG titers. These observations could be relevant to clinical CMV risk stratification, and they provide new insights into the mechanisms of the adaptive immune response against CMV infection in kidney transplantation.