A phase IV, open-label three-arm study investigating the impact of a combination of tenofovir disoproxil fumarate/emtricitabine with raltegravir or dolutegravir or elvitegravir/cobicistat on renal function in HIV-1 antiretroviral naïve patients

Objectives: Tenofovir DF (TDF) remains one of the preferred backbone agents for naïve HIV patients starting antiretroviral treatment (ART). The impact of TDF on renal function and metabolic parameters may vary by anchor agent. We investigated the impact of TDF in combination with 3 different integrase inhibitors on tubular and glomerular function, and metabolic parameters in ART-naïve patients. Methods: Sixty patients with normal renal function were randomised (20 per arm) to TDF/emtricitabine (FTC) plus either raltegravir (RAL) (400 mg b.d.), dolutegravir (DTG) or elvitegravir/cobicistat (EVG/c) for 48 weeks. Results: 57 patients completed the study. Significant increases in RBP/creatinine ratio at week 24 were seen in all arms [RAL +4.7 μg/mmol (CI 0.43 to 8.98, p = 0.032); DTG +4.96 μg/mmol (CI 0.77 to 9.15, p = 0.021); EVG/c +6.95 μg/mmol (CI 2.53 to 11.36, p = 0.002)], although this was not sustained to week 48 in the RAL arm. Similar changes across the arms were observed for urinary α1microglobulin (RAL +6.20 mg/L, p = 0.030; DTG +6.30 mg/L, p = 0.025; EVG/c +8.15 mg/L, p = 0.003). Urinary β2microglobulin significantly increased at week 24 with DTG and EVG/c but remained unchanged in the RAL arm. Glomerular filtration measured with CKD-EPI creatinine-cystatin C increased significantly in the RAL arm at week 24 through 48 but declined modestly in other two arms. Total and LDL cholesterol decreased in the RAL arm, but increased in the EVG/c arm, with no significant changes in the DTG arm. Weight increased significantly from baseline with DTG but not RAL or EVG/c. Conclusion: INSTIs in combination with TDF/FTC impact differently on tubular microproteinuria, eGFR, metabolic markers and weight. Use of TDF/FTC with RAL had the least tubular effects and the most favorable metabolic profile

Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial

Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing—termed kick and kill regimens—have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir. Methods: This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18–60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4+ T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074. Findings: Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log10 copies HIV DNA per 106 CD4+ T-cells in the ART-only group versus 3·06 log10 copies HIV DNA per 106 CD4+ T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log10 copies HIV DNA per 106 CD4+ T-cells [95% CI −0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events. Interpretation: This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required. Funding: Medical Research Council (MR/L00528X/1)