No Efficacy of the Combination of Lopinavir/Ritonavir Plus Hydroxychloroquine Versus Standard of Care in Patients Hospitalized With COVID-19: A Non-Randomized Comparison.

Objectives: No specific treatment has been approved for COVID-19. Lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) have been used with poor results, and a trial showed advantages of combined antiviral therapy vs. single antivirals. The aim of the study was to assess the effectiveness of the combination of antivirals (LPV/r and HCQ) or their single use in COVID-19 hospitalized patients vs. standard of care (SoC). Methods: Patients ≥18 years with SARS-CoV-2 infection, defined as positive RT-PCR from nasal/oropharyngeal (NP/OP) swab or positive serology, admitted at L. Spallanzani Institute (Italy) were included. Primary endpoint: time to invasive ventilation/death. Secondary endpoint: time to two consecutive negative SARS-CoV-2 PCRs in NP/OP swabs. In order to control for measured confounders, a marginal Cox regression model with inverse probability weights was used. Results: A total of 590 patients were included in the analysis: 36.3% female, 64 years (IQR 51-76), and 91% with pneumonia. Cumulative probability of invasive ventilation/death at 14 days was 21.2% (95% CI 17.6, 24.7), without difference between SOC, LPV/r, hydroxychloroquine, HCQ + LPV/r, and SoC. The risk of invasive ventilation/death in the groups appeared to vary by baseline ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Overall cumulative probability of confirmed negative nasopharyngeal swabs at 14 days was 44.4% (95% CI 38.9, 49.9), without difference between groups. Conclusion: In this retrospective analysis, we found no difference in the rate of invasive ventilation/death or viral shedding by different strategies, as in randomized trials performed to date. Moreover, even the combination HCQ + LPV/r did not show advantages vs. SoC.

A 15-year experience of two hundred and twenty five consecutive right hepatectomies.

BACKGROUND: In case of liver tumor, surgical resection is the therapeutic gold standard to increase patient survival. Among liver resections, right hepatectomy (RH) is defined as a major hepatectomy. The first aim of this study was to analyze the overall morbidity and mortality of patients undergoing RH, the second aim was to assess changes in both patients characteristic and surgical parameters and mortality rates in a single center institution. MATERIALS: From 2001 to December 2015, 225 RH were performed in our center. We analyzed two time period: 2001-2007 and 2008-2015. RESULTS: Ninety days post operative mortality was observed in 9 cases (4%) for the overall cohort. We observed a difference between the two groups in the use of Pringle Maneuver (p<0,001). This result is consistent in each major surgical indication: HCC (p=0,001), CLM (p=0,015) and BT (p=0,015). The estimated blood losses improved (p=0,028), particularly for the HCC cases (p=0,024). No difference was observed in terms of number of transfusions received between the two groups. Reduced length of stay was observed in the second group (p<0,001), more markedly for CLM cases (p=0,001). CONCLUSION: To further improve the outcomes of RH, it is important to performed this major hepatectomy in hepatobiliary centers with an overall liver resection experience of at least few hundred cases.

ALPPS for primary and secondary liver tumors.

INTRODUCTION: To report our experience on associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in patients with liver tumors. METHODS: ALPPS is a surgical technique that allows hepatic resection after rapid liver hypertrophy. RESULTS: Thirteen operations were performed: 8 for hepatocellular carcinoma (HCC) with liver cirrhosis (LC) and 5 for colorectal liver metastases (CRLM, n = 3) and cholangiocarcinoma (CC, n = 2) in normal livers (NL). Of the 11 men (85%), the median age was 60 years (range 36-74). Six (75%) HCC patients had BCLC stage C and 2 (25%) had BCLC stage B disease. The median % future liver remnant (FLR) volume increase was 71.7% in patients with LC and 64.8% in NL (p = 0.44). Twelve patients achieved a sufficient FLR growth after the first stage (92.3% efficacy). Four right trisectorectomies and 9 right hepatectomies were performed. All patients completed the second stage (100% feasibility). R0 resection was achieved in all cases. The 90-day mortality rate was 23.1% (12.5% for HCC patients with LC vs 40% for CRLM and CC patients with NL, p = 0.13). After the first stage the overall morbidity rates were 62.5% and 80% (p = 0.61), whereas after the second stage they were 87.5% and 80% in patients with LC and NL respectively (p = 0.99). At a median follow-up of 15 months (range 1-27), the median DFS was 9 months (CI95% 6-12), and the 1yr-DFS was 42%. The median survival was 25 months (CI95% 10-40), and the 1-yr overall survival was 74%. CONCLUSIONS: ALPPS induced a considerable and comparable FLR growth in HCC patients with liver cirrhosis and patients with CRLM and CC with normal liver parenchyma. HCC patients who underwent ALPPS had a high rate of macrovascular tumor involvement. A high rate of R0 resection is expected in properly selected patients.

Plasma HIV RNA decline and emergence of drug resistance mutations among patients with multiple virologic failures receiving resistance testing-guided HAART.

Early recognition of virologic failure in patients with extensive drug resistance receiving salvage-HAART is essential to avoid exposure to subinhibitory regimens. We studied plasma viral load (PVL) decline and rates of drug-resistance mutation (DRM) accumulation in such patients. A prospective, 48 week study of 38 heavily pretreated patients receiving genotypic resistance testing (GRT)-guided HAART was conducted. The rate of PVL decline was studied by weekly PVL determinations. To assess DRM accumulation, serial GRTs were performed in all nonresponders (never reaching PVL <50 or two PVLs >50 copies/ml after suppression). Over 48 weeks, 10 patients (26%) were nonresponders. Receiving less then two fully active drugs and having an elevated number of PI and NRTI mutations at baseline were strongly associated with virologic failure. There was no evidence of a difference in the change from baseline PVL to week 1 and 2 between responders and nonresponders. By contrast, PVL reductions from week 2 to week 3 and thereafter were significantly greater for responders (p < 0.01). Among nonresponders, the incidence rates per patient-month (95% CI) of emergent DRM were 0.67 (0.13-1.20), 0.40 (0.00-0.74), and 0.37 (0.00-0.75) at weeks 4, 8, and 24, respectively. Having limited baseline resistance, receiving at least two fully active drugs, and showing constant PVL reductions from week 2 to week 3 and thereafter were predictive of virologic response. In contrast, early changes in PVL levels were not. Virologic failure was associated with detection of emergent DRMs. Virologic rebound in patients on salvage-HAART should be addressed aggressively.

Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort.

BACKGROUND: Hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) was described in association with reverse-transcriptase (RT) mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs). We evaluated the effect of RT mutations associated with hypersusceptibility to NNRTIs on the response to efavirenz-based therapy. METHODS: We analyzed an observational database of patients for whom highly active antiretroviral therapy failed and who received genotypic resistance testing-guided therapy, either efavirenz or protease inhibitor (PI) based. Study end points were achievement of virus load <80 copies/mL, achievement of virus load <80 copies/mL without rebound to >500 copies/mL, and changes in CD4 cell counts. RESULTS: The baseline RT mutations M41L, M184V, L210W, and T215Y and the M41L/T215Y and M41L/T215Y/M184V combinations were associated with virological suppression for efavirenz-treated patients, whereas, for PI-treated patients, only the M184V mutation was associated with virological suppression, and the L210W mutation showed a negative correlation; no correlation was found between any mutation and virological response without rebound. CONCLUSIONS: The M41L, M184V, L210W, and T215Y mutations were associated with a better, although transient, virological outcome in patients treated with efavirenz-based regimens.