Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy

BACKGROUND: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. OBJECTIVES: To assess if we had missed low frequency mutations, using a more sensitive methodology. STUDY DESIGN: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. RESULTS: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DISCUSSION: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations

Universal bifurcation property of two- or higher-dimensional dissipative systems in parameter space: Why does 1D symbolic dynamics work so well?

The universal bifurcation property of the H\'enon map in parameter space is studied with symbolic dynamics. The universal-$L$ region is defined to characterize the bifurcation universality. It is found that the universal-$L$ region for relative small $L$ is not restricted to very small $b$ values. These results show that it is also a universal phenomenon that universal sequences with short period can be found in many nonlinear dissipative systems.Comment: 10 pages, figures can be obtained from the author, will appeared in J. Phys.

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT).

BACKGROUND: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. METHODS: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. FINDINGS: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. INTERPRETATION: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Incidental cardiac findings on computed tomography imaging of the thorax

<p>Abstract</p> <p>Background</p> <p>Investigation of pulmonary pathology with computed tomography also allows visualisation of the heart and major vessels. We sought to explore whether clinically relevant cardiac pathology could be identified on computed tomography pulmonary angiograms (CTPA) requested for the exclusion of pulmonary embolism (PE). 100 consecutive CT contrast-enhanced pulmonary angiograms carried out for exclusion of PE at a single centre were assessed retrospectively by two cardiologists.</p> <p>Findings</p> <p>Evidence of PE was reported in 5% of scans. Incidental cardiac findings included: aortic wall calcification (54%), coronary calcification (46%), cardiomegaly (41%), atrial dilatation (18%), mitral annulus calcification (15%), right ventricular dilatation (11%), aortic dilatation (8%) and right ventricular thrombus (1%). Apart from 3 (3%) reports describing cardiomegaly, no other cardiac findings were described in radiologists' reports. Other reported pulmonary abnormalities included: lung nodules (14%), lobar collapse/consolidation (8%), pleural effusion (2%), lobar collapse/consolidation (8%), emphysema (6%) and pleural calcification (4%).</p> <p>Conclusions</p> <p>CTPAs requested for the exclusion of PE have a high yield of cardiac abnormalities. Although these abnormalities may not have implications for acute clinical management, they may, nevertheless, be important in long-term care.</p