Switching to coformulated rilpivirine (RPV), emtricitabine (FTC) and tenofovir alafenamide from either RPV, FTC and tenofovir disoproxil fumarate (TDF) or efavirenz, FTC and TDF: 96-week results from two randomized clinical trials.

OBJECTIVES: The single-tablet regimen rilpivirine, emtricitabine and tenofovir alafenamide (RPV/FTC/TAF) for treatment of HIV-1-infected adults was approved based on bioequivalence. We assessed the clinical efficacy, safety and tolerability of switching to RPV/FTC/TAF from either RPV/FTC/tenofovir disoproxil fumarate (TDF) or efavirenz (EFV)/FTC/TDF. METHODS: We conducted two distinct randomized, double-blind, active-controlled, noninferiority trials in participants taking RPV/FTC/TDF (Study 1216) and EFV/FTC/TDF (Study 1160). Each study randomized virologically suppressed (HIV-1 RNA < 50 copies/mL) adults (1:1) to switch to RPV/FTC/TAF or continue their current regimen for 96 weeks. We evaluated efficacy as the proportion with HIV-1 RNA < 50 copies/mL using the Food and Drug Administration snapshot algorithm and prespecified bone and renal endpoints at week 96. RESULTS: We randomized and treated 630 participants in Study 1216 (RPV/FTC/TAF, n = 316; RPV/FTC/TDF, n = 314) and 875 in Study 1160 (RPV/FTC/TAF, n = 438; EFV/FTC/TDF, n = 437). In both studies, the efficacy of switching to RPV/FTC/TAF was noninferior to that of continuing baseline therapy at week 96, with respective percentages of patients with HIV RNA < 50 copies/mL being 89.2% versus 88.5% in Study 1216 [difference 0.7%; 95% confidence interval (CI) -4.3 to +5.8%] and 85.2% versus 85.1% in Study 1160 (difference 0%; 95% CI -4.8 to +4.8%). No participant on RPV/FTC/TAF developed treatment-emergent resistance versus two on EFV/FTC/TDF and one on RPV/FTC/TDF. Compared with continuing baseline therapy, significant improvements in bone mineral density and renal tubular markers were observed in the RPV/FTC/TAF groups (P < 0.001). CONCLUSIONS: Switching to RPV/FTC/TAF from RPV/FTC/TDF or EFV/FTC/TDF was safe and effective and improved bone mineral density and renal biomarkers up to 96 weeks with no cases of treatment-emergent resistance.

CD36 is upregulated in mice with periodontitis and metabolic syndrome and involved in macrophage gene upregulation by palmitate.

BACKGROUND: We reported that high-fat diet (HFD)-induced metabolic syndrome (MetS) exacerbates lipopolysaccharide (LPS)-stimulated periodontitis and palmitate, the major saturated fatty acid in the HFD, amplified LPS-stimulated gene expression in vitro. As CD36 is a major receptor for fatty acids, we investigated periodontal CD36 expression in mice with periodontitis and MetS, and the role of CD36 in inflammatory gene expression in macrophages stimulated by palmitate. METHODS: MetS and periodontitis were induced in mice by HFD and periodontal injection of LPS, respectively. The periodontal CD36 expression and its relationship with alveolar bone loss were studied using immunohistochemistry, real-time PCR, and correlation analysis. The role of CD36 in upregulation of inflammatory mediators by LPS and palmitate in macrophages was assessed using pharmacological inhibitor and small interfering RNA. RESULTS: Periodontal CD36 expression was higher in mice with both MetS and periodontitis than that in mice with periodontitis or MetS alone and was correlated with osteoclastogenesis and alveolar bone loss. In vitro studies showed that CD36 expression in macrophages was upregulated by LPS and palmitate, and targeting CD36 attenuated palmitate-enhanced gene expression. CONCLUSION: CD36 expression is upregulated in mice with periodontitis and MetS and involved in gene expression in macrophages stimulated by palmitate and LPS.

Statin intake is associated with MMP-1 level in gingival crevicular fluid of patients with periodontitis.

BACKGROUND: This study was conducted to assess whether statin intake is associated with clinical parameters of periodontitis and matrix metalloproteinase (MMP) levels in gingival crevicular fluid (GCF) of non-diabetic and diabetic patients. METHODS: We first determined the effect of simvastatin on MMP expression in mononuclear cells. We then recruited 117 non-diabetic and diabetic patients, who all had periodontitis and took or did not take statin, and measured periodontal probing depth (PPD) and clinical attachment level (CAL), and collected gingival crevicular fluid (GCF) to quantify MMPs. RESULTS: The in vitro studies showed that simvastatin potently inhibited the expression of MMP-1, MMP-8, and MMP-9 upregulated by lipopolysaccharide (LPS) and high glucose in mononuclear cells. The patient study showed that, after adjusting for age and smoking status, PPD in diabetic patients on statin was significantly less than that in diabetic patients not on statin. MMP-1 level in GCF of non-diabetic and diabetic patients on statin was lower than that of non-diabetic and diabetic patients not on statin, respectively. No difference was found for MMP-8 and -9 levels in GCF. CONCLUSION: Statin intake is associated with reduced PPD in diabetic patients and MMP-1 level in GCF in either non-diabetic or diabetic patients.

The Intelence aNd pRezista Once A Day Study (INROADS): a multicentre, single-arm, open-label study of etravirine and darunavir/ritonavir as dual therapy in HIV-1-infected early treatment-experienced subjects.

OBJECTIVES: Following antiretroviral therapy failure, patients are often treated with a three-drug regimen that includes two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. An alternative two-drug nucleoside-sparing regimen may decrease the pill burden and drug toxicities associated with the use of N(t)RTIs. The Intelence aNd pRezista Once A Day Study (INROADS; NCT01199939) evaluated the nucleoside-sparing regimen of etravirine 400 mg with darunavir/ritonavir 800/100 mg once-daily in HIV-1-infected treatment-experienced subjects or treatment-naïve subjects with transmitted resistance. METHODS: In this exploratory phase 2b, single-arm, open-label, multicentre, 48-week study, the primary endpoint was the proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at week 48 [confirmed virological response (CVR), non-virological failure (VF) censored]. Key secondary endpoints included assessments of changes from baseline to week 48 in viral load, immunological response, pharmacokinetics/pharmacodynamics, safety, tolerability, metabolic and bone markers and body fat. RESULTS: Forty-one of the 54 enrolled subjects completed the study. Adverse events (7%) and VF (7%) were the most common reasons for discontinuation. The week 48 CVR rate in the intent-to-treat (ITT) non-VF censored population was 89% (primary endpoint). Seven subjects experienced VF. Common adverse events were diarrhoea (15%), rash (15%) and upper respiratory tract infection (11%). Mild/moderate lipid elevations, minimal changes in limb fat distribution and bone mineral density and no clinically relevant changes in glucose metabolism were observed. CONCLUSIONS: Etravirine 400 mg and darunavir/ritonavir 800/100 mg as a two-drug once-daily regimen in treatment-experienced subjects or treatment-naïve subjects with transmitted resistance was virologically efficacious and well tolerated.

Switching from twice-daily raltegravir plus tenofovir disoproxil fumarate/emtricitabine to once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate in virologically suppressed, HIV-1-infected subjects: 48 weeks data.

BACKGROUND: Pill burden, dosing frequency, and concerns about safety and tolerability are important obstacles to maintaining adequate medication adherence. Raltegravir (RAL) is indicated for twice-daily dosing and when taken with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), it becomes a twice-daily multiple-tablet regimen. Elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF, STB, is the first approved once-a-day integrase strand transfer inhibitor (INSTI) containing single-tablet regimen that combines EVG, an INSTI, and COBI, a novel pharmacoenhancer, with the preferred nucleos(t)ide backbone of FTC/TDF. METHODS: This was a 48-week prospective, single-arm open-label study of the switch to STB in virologically sup-pressed HIV-1-infected adult patients on FTC/TDF and twice-daily RAL for at least 6 months. Objectives were to evaluate the tolerability and safety of a regimen simplification to once-a-day STB, while maintaining viral suppression through 48 weeks. RESULTS: Forty-eight individuals in the United States were enrolled. The median age was 44 years, 96% were male, and 83% were White. The median time on RAL + FTC/TDF treatment prior to enrollment was 34 months. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At base-line, the median CD4 count was 714 cell/µL and estimated glomerular filtration rate (eGFR) was 105 mL/min. At week 48, all assessed study participants remained viro-logically suppressed to the lower limit of quantification (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min). STB was well tolerated with no discontinuations, no study drug-related serious adverse events, and no study drug-related grade 3/4 adverse events. CONCLUSIONS: All participants switching to 1 tablet once-a-day STB from a twice-daily RAL + FTC/TDF regimen remained virologically suppressed. STB was well tolerated. Switching to STB may be a viable option for virologically suppressed patients wanting to simplify from a twice-daily RAL-containing regimen.

SWIFT: prospective 48-week study to evaluate efficacy and safety of switching to emtricitabine/tenofovir from lamivudine/abacavir in virologically suppressed HIV-1 infected patients on a boosted protease inhibitor containing antiretroviral regimen.

BACKGROUND: In the United States, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone with lamivudine/abacavir (3TC/ABC) as a commonly used alternative. For patients infected with human immunodeficiency virus (HIV-1) virologically suppressed on a boosted protease inhibitor (PI) + 3TC/ABC regimen, the merits of switching to FTC/TDF as the NRTI backbone are unknown. METHODS: SWIFT was a prospective, randomized, open-label 48-week study to evaluate efficacy and safety of switching to FTC/TDF. Subjects receiving 3TC/ABC + PI + ritonavir (RTV) with HIV-1 RNA < 200 c/mL ≥3 months were randomized to continue 3TC/ABC or switch to FTC/TDF. The primary endpoint was time to loss of virologic response (TLOVR) with noninferiority measured by delta of 12%. Virologic failure (VF) was defined as confirmed rebound or the last HIV-1 RNA measurement on study drug ≥200 c/mL. RESULTS: In total, 311 subjects were treated in this study (155 to PI + RTV + FTC/TDF, 156 to PI + RTV + 3TC/ABC). Baseline characteristics were similar between the arms: 85% male, 28% black, median age, 46 years; and median CD4 532 cells/mm(3). By TLOVR through week 48, switching to FTC/TDF was noninferior compared to continued 3TC/ABC (86.4% vs 83.3%, treatment difference 3.0% (95% confidence interval, -5.1% to 11.2%). Fewer subjects on FTC/TDF experienced VF (3 vs 11; P = .034). FTC/TDF showed greater declines in fasting low-density lipoproteins (LDL), total cholesterol (TC), and triglycerides (TG) with significant declines in LDL and TC beginning at week 12 with no TC/HDL ratio change. Switching to FTC/TDF showed improved NCEP thresholds for TC and TG and improved 10-year Framingham TC calculated scores. Decreased estimated glomerular filtration rate [corrected] (eGFR) was observed in both arms with a larger decrease in the FTC/TDF arm. CONCLUSIONS: Switching to FTC/TDF from 3TC/ABC maintained virologic suppression, had fewer VFs, improved lipid parameters and Framingham scores but decreased eGFR. CLINICALTRIALS.GOV IDENTIFIER: NCT00724711.

The role of human papillomavirus deoxyribonucleic acid assay and repeated cervical cytologic examination in the detection of cervical intraepithelial neoplasia among human immunodeficiency virus-infected women. Cervical Disease Study Group of the American Foundation for AIDS Research Community Based Clinical Trials Network.

OBJECTIVES: We sought to measure the characteristics of a quantitative human papillomavirus deoxyribonucleic acid assay and repeated cervical cytologic examination in screening for cervical intraepithelial neoplasia among human immunodeficiency virus-infected women. STUDY DESIGN: Human immunodeficiency virus-infected women with screening CD4+ lymphocyte counts of < or = 500 cells/mm3 (n = 103) were examined by quantitative human papillomavirus deoxyribonucleic acid assay and serial cervical cytologic examination and by colposcopy with biopsy and endocervical curettage during the course of 1 year. RESULTS: Quantitative measures of total human papillomavirus deoxyribonucleic acid and high-risk human papillomavirus deoxyribonucleic acid were strongly associated with any cervical intraepithelial neoplasia (P = .005) and high-grade cervical intraepithelial neoplasia (P = .0006), but they improved the sensitivity and negative predictive value of baseline screening only slightly when combined with cervical cytologic examination. Incident cervical intraepithelial neoplasia occurred frequently (20%) during 1 year of follow-up and was more common among human papillomavirus-infected women. Repeated cytologic examination identified 60% of women with new cervical intraepithelial neoplasia. CONCLUSION: Human immunodeficiency virus-infected women with at least mild immunosuppression have a high incidence of cervical intraepithelial neoplasia, which warrants close follow-up. Those with high baseline human papillomavirus deoxyribonucleic acid levels may be at the highest risk for incident cervical intraepithelial neoplasia.