Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI.

BACKGROUND: Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills. OBJECTIVE: We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens. METHODS: STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min. RESULTS: At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7-26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating). CONCLUSION: E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.

Simplification to Stribild vs continuation of RTV-boosted DRV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY-PI subgroup analysis.

INTRODUCTION: Simplification to Stribild (STB) was statistically superior to continuation of a ritonavir-boosted protease inhibitor (PI+RTV) with emtricitabine and tenofovir DF (FTC/TDF) at week (W) 48 in virologically suppressed HIV adults (1). We report the W48 efficacy and safety of STB versus RTV-boosted darunavir (DRV) with FTC/TDF in suppressed subjects. MATERIAL AND METHODS: Virologically suppressed subjects on PI+RTV with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB vs continue their PI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at W48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by PI use (DRV [173], atazanavir [174], lopinavir [72], Other PI [13]) at screening was pre-specified. RESULTS: Four hundred twenty-nine subjects were randomized and treated (mITT set). In the DRV subgroup, 113 switched to STB; 60 continued a RTV-boosted DRV with FTC/TDF. At W48, 95% STB versus 92% DRV maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. Median increases from baseline in CD4 count at week 48 (cells/µL): 28 STB versus 29 DRV (p=0.81). Discontinuations due to adverse events were 3% STB versus 2% DRV; one case of isolated decrease in eGFR in the DRV group and no cases of proximal renal tubulopathy in either group. There were statistically significant decreases in the frequency of diarrhoea reported on the HIV Symptom Index at week 4 to week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB vs DRV group; median changes (mL/min) at week 48: -8.5 vs -0.6, consistent with the known cobicistat inhibition of renal creatinine secretion. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: -15 to 15) at week 4 (median: 12 vs 9; p=0.006) and week 24 (median: 13 vs 8; p=0.001). CONCLUSIONS: In this small group of virologically suppressed subjects, simplification to STB versus continuation of a RTV-boosted DRV with FTC/TDF was safe, well-tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.

Murine models of Streptococcus pyogenes infection.

This unit describes procedures for testing virulence of Streptococcus pyogenes in mice. S. pyogenes is an important human pathogen and causes one of the most common childhood diseases. The syndromes that result from S. pyogenes infection are diverse, ranging from mild, superficial throat or skin infection to severe, invasive disea/se that is often lethal. Thus, a greater understanding of the virulence factors of this bacterium and development of modalities to prevent or relieve the infections it causes are important. Since S. pyogenes is a strictly human pathogen (with the exception of a single strain), the value of all animal models is limited. This unit describes a model for long-term throat colonization following the natural route of infection (inhalation), one for pneumonia and systemic dissemination following intratracheal inoculation, and one for systemic dissemination following the more natural route of skin infection. In addition, methods are presented for culturing S. pyogenes from tissues of the infected animal.